ADRB2 encodes the beta-2 adrenergic receptor, a seven-transmembrane catecholamine GPCR that acts mainly at the plasma membrane. Epinephrine and norepinephrine binding activate bifurcated G protein signaling, especially Gs/cAMP/PKA and context-dependent Gi branches, with downstream effects on MAPK signaling, smooth-muscle and cardiovascular physiology, thermogenesis, and adipocyte lipolysis. Activated receptors are regulated by arrestin- and ubiquitin-dependent endocytosis, recycling, lysosomal sorting, and Golgi-associated palmitoylation-dependent trafficking. Beyond terminating signaling, internalized beta-arrestin-bound receptors can sustain G protein signaling from endosomes, so receptor output is shaped by subcellular location as well as ligand.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Positive regulation of MAPK cascade is a supported ADRB2 signaling branch.
Reason: ADRB2 activates ERK/MAPK through beta-arrestin/Src/EGFR-associated receptor complexes, so this is a real receptor signaling output rather than a project-level inference.
GO:0002025
norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure
IBA
GO_REF:0000033
KEEP AS NON CORE
Summary: Systemic blood-pressure vasodilation is plausible phylogenetic physiology context, but not a core ADRB2 molecular function.
Reason: This IBA row is retained as non-core physiology context from phylogenetic/curated annotation. The cached MARCH2 paper only provides background about vascular tone and is not used as experimental support for this term; the local review does not identify direct human ADRB2 vasodilation experiments among the cached sources.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
Summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
Reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
Summary: Norepinephrine binding is supported as part of the catecholamine receptor activity.
Reason: ADRB2 binds catecholamines including norepinephrine, although epinephrine has higher affinity. This ligand-binding term supports the core beta-2 adrenergic receptor activity.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
ADRB2 binds epinephrine (Epi) with an
file:human/ADRB2/ADRB2-uniprot.txt
approximately 30-fold greater affinity than norepinephrine (NE)
Summary: Generic adrenergic receptor activity is correct but less specific than beta2-adrenergic receptor activity.
Reason: ADRB2 is specifically the beta-2 adrenergic receptor, so the specific child term should be used rather than a broader adrenergic receptor activity term.
Summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
Reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
Summary: Golgi apparatus is a supported receptor itinerary location but not the primary active signaling location.
Reason: Activated ADRB2 can traffic through the Golgi in a palmitoylation-dependent itinerary, but the primary core location for receptor signaling is the plasma membrane.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
expression of the human beta 2-adrenergic receptor in mouse L cells
GO:0006940
regulation of smooth muscle contraction
IEA
GO_REF:0000002
MARK AS OVER ANNOTATED
Summary: Regulation of smooth muscle contraction is broad vascular physiology context and is not directly supported by the cached ADRB2 experiments.
Reason: The previous MARCH2 citation was introductory background rather than experimental support. Because the cached evidence directly supports ADRB2 receptor signaling and trafficking rather than smooth-muscle contraction regulation, this broad IEA physiology row should be treated as over-annotated.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
GO:0007186
G protein-coupled receptor signaling pathway
IEA
GO_REF:0000002
MODIFY
Summary: Generic GPCR signaling is too broad for ADRB2.
Reason: Replace the broad GPCR signaling pathway with adrenergic receptor signaling and, where appropriate, the adenylate cyclase-activating adrenergic receptor signaling pathway.
Summary: Blood vessel diameter maintenance is broad vascular physiology context and is not directly supported by the cached ADRB2 experiments.
Reason: The previous MARCH2 citation was introductory background rather than experimental support. The reviewed evidence supports catecholamine receptor signaling, but not a direct ADRB2-specific blood-vessel-diameter maintenance assay, so this IEA row is over-annotated.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
IPI
PMID:17148612
A system for quantifying dynamic protein interactions define...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:17170700
Dosage-dependent switch from G protein-coupled to G protein-...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:20353789
Beta-2 adrenergic receptor mediated ERK activation is regula...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:23208550
Distinct roles for β-arrestin2 and arrestin-domain-containin...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:23236378
Mammalian α arrestins link activated seven transmembrane rec...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:23291003
Adenosine A1 receptors heterodimerize with β1- and β2-adrene...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:28298427
Systematic protein-protein interaction mapping for clinicall...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:36115835
Quantitative fragmentomics allow affinity mapping of interac...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:39083597
Multiplexed mapping of the interactome of GPCRs with recepto...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:9671706
A C-terminal motif found in the beta2-adrenergic receptor, P...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:15518545
Biochemical and biophysical characterization of serotonin 5-...
KEEP AS NON CORE
Summary: Identical protein binding reflects receptor oligomerization, but it is not ADRB2 core function.
Reason: ADRB2 oligomerization/hetero-oligomerization is supported, but the core molecular function remains catecholamine receptor activity and downstream GPCR signaling.
IPI
PMID:19763081
Ligand-regulated oligomerization of beta(2)-adrenoceptors in...
KEEP AS NON CORE
Summary: Identical protein binding reflects receptor oligomerization, but it is not ADRB2 core function.
Reason: ADRB2 oligomerization/hetero-oligomerization is supported, but the core molecular function remains catecholamine receptor activity and downstream GPCR signaling.
IPI
PMID:20590567
Physical and functional interaction between CB1 cannabinoid ...
KEEP AS NON CORE
Summary: Identical protein binding reflects receptor oligomerization, but it is not ADRB2 core function.
Reason: ADRB2 oligomerization/hetero-oligomerization is supported, but the core molecular function remains catecholamine receptor activity and downstream GPCR signaling.
Summary: Nucleus is not supported as a primary ADRB2 location.
Reason: The reviewed UniProt and publication evidence supports plasma membrane, endosomal/lysosomal trafficking, and Golgi itinerary contexts, not a nuclear ADRB2 location.
Summary: Adenylate cyclase binding is supported as receptor-effector complex context but is not the core MF term.
Reason: ADRB2 can associate with adenylyl cyclase and channel-effector complexes, but beta2-adrenergic receptor activity is the more direct core molecular function.
beta(2)AR interacts directly with Kir3.1/3.4 and Kir3.1/3.2c heterotetramers as well as with adenylyl cyclase
GO:0010666
positive regulation of cardiac muscle cell apoptotic process
IEA
GO_REF:0000107
KEEP AS NON CORE
Summary: Positive regulation of cardiac muscle cell apoptosis is a context-specific signaling output.
Reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context outputs rather than the core receptor activity.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte
file:human/ADRB2/ADRB2-uniprot.txt
Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction rate
GO:0010667
negative regulation of cardiac muscle cell apoptotic process
IEA
GO_REF:0000107
KEEP AS NON CORE
Summary: Negative regulation of cardiac muscle cell apoptosis is a context-specific signaling output.
Reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context outputs rather than the core receptor activity.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte
file:human/ADRB2/ADRB2-uniprot.txt
Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction rate
Summary: Apical plasma membrane is plausible specialized plasma-membrane context, but not the primary localization term.
Reason: ADRB2 is primarily a plasma-membrane GPCR; apical plasma membrane can be retained as cell-type context but should not replace the core plasma membrane annotation.
Summary: Generic enzyme binding is not an informative ADRB2 molecular function.
Reason: ADRB2 has specific signaling and trafficking partners, but generic enzyme binding should not be used as a functional endpoint when beta2-adrenergic receptor activity and specific pathway terms are available.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Specific interaction contexts such as receptor oligomerization
GO:0061885
positive regulation of mini excitatory postsynaptic potential
IEA
GO_REF:0000107
KEEP AS NON CORE
Summary: Positive regulation of mini excitatory postsynaptic potential is a neuronal downstream context.
Reason: The amyloid-beta/AMPA receptor study supports a neuronal beta2AR signaling complex affecting excitatory postsynaptic currents, but this is a specialized context rather than the core ADRB2 function.
Summary: Adenylate cyclase-inhibiting adrenergic receptor signaling is supportable as the Gi arm of ADRB2 signaling.
Reason: UniProt describes ADRB2 coupling to both Gs and Gi proteins; the Gi branch is part of bifurcated beta-2 adrenergic receptor signaling even if it is more context-dependent than the canonical Gs/cAMP arm.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
Summary: Neuronal dense core vesicle is not supported as a primary ADRB2 active location.
Reason: The local evidence supports plasma membrane receptor activity and endosomal/Golgi trafficking. Dense-core vesicle activity is not established by the reviewed ADRB2 publications.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
SUBCELLULAR LOCATION: Cell membrane
GO:0106134
positive regulation of cardiac muscle cell contraction
IEA
GO_REF:0000107
KEEP AS NON CORE
Summary: Positive regulation of cardiac muscle cell contraction is a downstream tissue-specific output.
Reason: Cardiomyocyte contraction-rate regulation is a physiological output of beta-adrenergic signaling and is secondary to the core receptor activity.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte
file:human/ADRB2/ADRB2-uniprot.txt
Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction rate
GO:0120162
positive regulation of cold-induced thermogenesis
IEA
GO_REF:0000107
MARK AS OVER ANNOTATED
Summary: Cold-induced thermogenesis is not supported as an ADRB2-specific annotation by the cited triple-knockout study.
Reason: PMID:12387862 tests beta1/beta2/beta3 adrenoceptor triple-knockout mice, so its cold-intolerance phenotype supports beta-adrenergic signaling broadly, not ADRB2 specifically. ADRB2-specific adipocyte evidence supports cAMP-stimulated lipolysis, but not direct positive regulation of cold-induced thermogenesis at the gene level.
Summary: Cellular response to amyloid-beta is a supported disease-context signaling response.
Reason: A beta binds beta2AR and induces PKA-dependent AMPA receptor hyperactivity, but this Alzheimer-disease-related context is not ADRB2 core physiology.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
EXP
PMID:20559325
Arrestin domain-containing protein 3 recruits the NEDD4 E3 l...
ACCEPT
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
EXP
PMID:25220262
Insights into β2-adrenergic receptor binding from structures...
ACCEPT
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
EXP
PMID:2831218
Site-directed mutagenesis and continuous expression of human...
ACCEPT
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
EXP
PMID:7915137
Amino-terminal polymorphisms of the human beta 2-adrenergic ...
ACCEPT
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
IGI
PMID:20395454
Binding of amyloid beta peptide to beta2 adrenergic receptor...
ACCEPT
Summary: Adrenergic receptor signaling pathway is a core ADRB2 signaling annotation.
Reason: ADRB2 transduces catecholamine binding into adrenergic receptor signaling through G protein, cAMP/PKA, beta-arrestin, and MAPK-associated branches.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
regulate adenylyl cyclase and extracellular signal-regulated kinase activity
GO:1900451
positive regulation of glutamate receptor signaling pathway
IGI
PMID:20395454
Binding of amyloid beta peptide to beta2 adrenergic receptor...
KEEP AS NON CORE
Summary: Positive regulation of glutamate receptor signaling is a neuronal amyloid-beta context.
Reason: The amyloid-beta study supports beta2AR/AMPA receptor complex signaling, but this is a specialized neuronal disease-context output rather than the central ADRB2 function.
Summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
Reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
IMP
PMID:2831218
Site-directed mutagenesis and continuous expression of human...
ACCEPT
Summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
Reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
IDA
PMID:19584355
Oxygen-regulated beta(2)-adrenergic receptor hydroxylation b...
ACCEPT
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
expression of the human beta 2-adrenergic receptor in mouse L cells
GO:0010666
positive regulation of cardiac muscle cell apoptotic process
ISS
GO_REF:0000024
KEEP AS NON CORE
Summary: Positive regulation of cardiac muscle cell apoptosis is a context-specific signaling output.
Reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context outputs rather than the core receptor activity.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte
file:human/ADRB2/ADRB2-uniprot.txt
Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction rate
GO:0010667
negative regulation of cardiac muscle cell apoptotic process
ISS
GO_REF:0000024
KEEP AS NON CORE
Summary: Negative regulation of cardiac muscle cell apoptosis is a context-specific signaling output.
Reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context outputs rather than the core receptor activity.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte
file:human/ADRB2/ADRB2-uniprot.txt
Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction rate
Summary: Adenylate cyclase-inhibiting adrenergic receptor signaling is supportable as the Gi arm of ADRB2 signaling.
Reason: UniProt describes ADRB2 coupling to both Gs and Gi proteins; the Gi branch is part of bifurcated beta-2 adrenergic receptor signaling even if it is more context-dependent than the canonical Gs/cAMP arm.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
GO:0106134
positive regulation of cardiac muscle cell contraction
ISS
GO_REF:0000024
KEEP AS NON CORE
Summary: Positive regulation of cardiac muscle cell contraction is a downstream tissue-specific output.
Reason: Cardiomyocyte contraction-rate regulation is a physiological output of beta-adrenergic signaling and is secondary to the core receptor activity.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte
file:human/ADRB2/ADRB2-uniprot.txt
Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction rate
IPI
PMID:20395454
Binding of amyloid beta peptide to beta2 adrenergic receptor...
KEEP AS NON CORE
Summary: Protein-containing complex binding is supported by the amyloid-beta/AMPA receptor complex context.
Reason: The amyloid-beta study supports beta2AR participation in a postsynaptic signaling complex, but this generic binding term is less informative than receptor activity and pathway-specific signaling terms.
IGI
PMID:20395454
Binding of amyloid beta peptide to beta2 adrenergic receptor...
KEEP AS NON CORE
Summary: AMPA-selective glutamate receptor signaling is a specialized neuronal output.
Reason: Beta2AR can mediate amyloid-beta-induced AMPA receptor hyperactivity, but this is a disease/neuron signaling branch rather than ADRB2 core function.
GO:0045744
negative regulation of G protein-coupled receptor signaling pathway
IDA
PMID:15123695
Hetero-oligomerization between beta2- and beta3-adrenergic r...
KEEP AS NON CORE
Summary: Negative regulation of GPCR signaling is supported as receptor regulation/desensitization context.
Reason: Hetero-oligomerization and beta-arrestin/endocytic regulation can dampen ADRB2 signaling, but the central function remains receptor activation of adrenergic signaling pathways.
IPI
PMID:23166351
MARCH2 promotes endocytosis and lysosomal sorting of carvedi...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IDA
PMID:23166351
MARCH2 promotes endocytosis and lysosomal sorting of carvedi...
ACCEPT
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
IDA
PMID:27481942
S-Palmitoylation of a Novel Site in the β2-Adrenergic Recept...
KEEP AS NON CORE
Summary: Golgi apparatus is a supported receptor itinerary location but not the primary active signaling location.
Reason: Activated ADRB2 can traffic through the Golgi in a palmitoylation-dependent itinerary, but the primary core location for receptor signaling is the plasma membrane.
IDA
PMID:27481942
S-Palmitoylation of a Novel Site in the β2-Adrenergic Recept...
ACCEPT
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
Reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
Summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
Reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
Summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
Reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
Summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
Reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
Summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
Reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
Summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
Reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
Summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
Reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation and sorting, but this is receptor lifecycle context rather than the core active signaling location.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes
GO:0120162
positive regulation of cold-induced thermogenesis
ISS
PMID:12387862
Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese...
MARK AS OVER ANNOTATED
Summary: Cold-induced thermogenesis is not supported as an ADRB2-specific annotation by the cited triple-knockout study.
Reason: PMID:12387862 tests beta1/beta2/beta3 adrenoceptor triple-knockout mice, so its cold-intolerance phenotype supports beta-adrenergic signaling broadly, not ADRB2 specifically. ADRB2-specific adipocyte evidence supports cAMP-stimulated lipolysis, but not direct positive regulation of cold-induced thermogenesis at the gene level.
IDA
PMID:20395454
Binding of amyloid beta peptide to beta2 adrenergic receptor...
KEEP AS NON CORE
Summary: Amyloid-beta binding is direct but disease-context and not a core ADRB2 function.
Reason: Soluble amyloid beta binding to beta2AR is experimentally supported, but it is a specialized Alzheimer-disease-related interaction rather than ADRB2 canonical catecholamine receptor function.
NAS
PMID:20395454
Binding of amyloid beta peptide to beta2 adrenergic receptor...
ACCEPT
Summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
Reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
IGI
PMID:20395454
Binding of amyloid beta peptide to beta2 adrenergic receptor...
KEEP AS NON CORE
Summary: Cellular response to amyloid-beta is a supported disease-context signaling response.
Reason: A beta binds beta2AR and induces PKA-dependent AMPA receptor hyperactivity, but this Alzheimer-disease-related context is not ADRB2 core physiology.
TAS
PMID:20395454
Binding of amyloid beta peptide to beta2 adrenergic receptor...
MARK AS OVER ANNOTATED
Summary: Response to psychosocial stress is too high-level for a direct ADRB2 gene annotation from the reviewed evidence.
Reason: The supporting ADRB2 evidence is receptor signaling and amyloid-beta neuronal signaling; a broad organismal psychosocial-stress response annotation is not a precise gene-product function.
IDA
PMID:19710023
Structure of an arrestin2-clathrin complex reveals a novel c...
ACCEPT
Summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
Reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
IDA
PMID:19710023
Structure of an arrestin2-clathrin complex reveals a novel c...
ACCEPT
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
IDA
PMID:19710023
Structure of an arrestin2-clathrin complex reveals a novel c...
ACCEPT
Summary: Adrenergic receptor signaling pathway is a core ADRB2 signaling annotation.
Reason: ADRB2 transduces catecholamine binding into adrenergic receptor signaling through G protein, cAMP/PKA, beta-arrestin, and MAPK-associated branches.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
Summary: Endosome membrane is a supported post-endocytic receptor trafficking location.
Reason: Internalized ADRB2 is sorted between recycling and lysosomal routes from endosomes, but this is secondary to the plasma-membrane receptor signaling role.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
expression of the human beta 2-adrenergic receptor in mouse L cells
GO:1901098
positive regulation of autophagosome maturation
IDA
PMID:23708524
β-adrenergic receptor-stimulated lipolysis requires the RAB7...
KEEP AS NON CORE
Summary: Positive regulation of autophagosome maturation is supported in ADRB2-stimulated adipocyte lipolysis but is non-core.
Reason: ADRB2 stimulation increases autophagy-targeted lipid droplets, but the direct lipophagy machinery in the paper is RAB7; therefore this is retained as an upstream adipocyte signaling output rather than a core ADRB2 function.
IDA
PMID:23708524
β-adrenergic receptor-stimulated lipolysis requires the RAB7...
KEEP AS NON CORE
Summary: Positive regulation of lipophagy is supported as upstream ADRB2 adipocyte signaling, but should not be upgraded to direct lipophagy.
Reason: The PN projection to direct lipophagy is not accepted for ADRB2. PMID:23708524 supports ADRB2 stimulation as an upstream signal that increases lipophagy/autophagy-targeted lipid droplets, while RAB7 is the direct lipid-droplet recruitment and autolysosomal degradation factor.
IPI
PMID:24405750
CNIH4 interacts with newly synthesized GPCR and controls the...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IDA
PMID:23382219
Structural basis for endosomal trafficking of diverse transm...
ACCEPT
Summary: Signaling receptor complex is a supported core context for ADRB2 signaling.
Reason: ADRB2 functions in receptor-effector and receptor-scaffold complexes that support beta-adrenergic signaling, including beta2/beta3 receptor signaling units and postsynaptic complexes.
IPI
PMID:20733053
SNX27 mediates PDZ-directed sorting from endosomes to the pl...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IPI
PMID:19424180
The deubiquitinases USP33 and USP20 coordinate beta2 adrener...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IDA
PMID:12297500
G protein-coupled receptors form stable complexes with inwar...
ACCEPT
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
IDA
PMID:12297500
G protein-coupled receptors form stable complexes with inwar...
KEEP AS NON CORE
Summary: Potassium channel regulator activity is supported receptor-effector context but not core ADRB2 function.
Reason: ADRB2 can form stable complexes with Kir3 potassium channels and adenylyl cyclase, but this specialized effector-complex role is secondary to beta2-adrenergic receptor activity.
IDA
PMID:9235896
A novel interaction between adrenergic receptors and the alp...
ACCEPT
Summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
Reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine binding, G protein coupling, and downstream signaling.
IDA
PMID:15123695
Hetero-oligomerization between beta2- and beta3-adrenergic r...
ACCEPT
Summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
Reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine binding, Gs/Gi coupling, and adenylate cyclase signaling.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
G protein-coupled receptor for catecholamines that couples to
file:human/ADRB2/ADRB2-uniprot.txt
both G(s) and G(i) proteins, activating bifurcated signaling pathways
IPI
PMID:15123695
Hetero-oligomerization between beta2- and beta3-adrenergic r...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
IDA
PMID:15123695
Hetero-oligomerization between beta2- and beta3-adrenergic r...
KEEP AS NON CORE
Summary: Receptor-mediated endocytosis is supported receptor lifecycle regulation.
Reason: Agonist-induced beta2AR internalization and down-regulation are well supported, but this is post-activation receptor trafficking rather than the primary receptor signaling function.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
IDA
PMID:15123695
Hetero-oligomerization between beta2- and beta3-adrenergic r...
ACCEPT
Summary: Signaling receptor complex is a supported core context for ADRB2 signaling.
Reason: ADRB2 functions in receptor-effector and receptor-scaffold complexes that support beta-adrenergic signaling, including beta2/beta3 receptor signaling units and postsynaptic complexes.
IDA
PMID:15123695
Hetero-oligomerization between beta2- and beta3-adrenergic r...
ACCEPT
Summary: Positive regulation of MAPK cascade is a supported ADRB2 signaling branch.
Reason: ADRB2 activates ERK/MAPK through beta-arrestin/Src/EGFR-associated receptor complexes, so this is a real receptor signaling output rather than a project-level inference.
IDA
PMID:15123695
Hetero-oligomerization between beta2- and beta3-adrenergic r...
ACCEPT
Summary: Norepinephrine binding is supported as part of the catecholamine receptor activity.
Reason: ADRB2 binds catecholamines including norepinephrine, although epinephrine has higher affinity. This ligand-binding term supports the core beta-2 adrenergic receptor activity.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
ADRB2 binds epinephrine (Epi) with an
file:human/ADRB2/ADRB2-uniprot.txt
approximately 30-fold greater affinity than norepinephrine (NE)
IPI
PMID:9560162
The beta2-adrenergic receptor interacts with the Na+/H+-exch...
MARK AS OVER ANNOTATED
Summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
Reason: The interaction records identify many receptor partners, but GO protein binding does not describe ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling, receptor-complex context, and specific trafficking or signaling outputs.
Supporting Evidence:
file:human/ADRB2/ADRB2-notes.md
Generic `protein binding` rows are not informative ADRB2 molecular functions
TAS
PMID:9507004
Role of clathrin-mediated endocytosis in agonist-induced dow...
KEEP AS NON CORE
Summary: Lysosome is a supported destination for down-regulated ADRB2.
Reason: Activated/internalized ADRB2 can be routed to lysosomes for degradation, but lysosome localization is receptor turnover context and not the core active signaling site.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
TAS
PMID:1371121
Ligand-regulated internalization and recycling of human beta...
MODIFY
Summary: Generic cell-surface receptor signaling is too broad for ADRB2.
Reason: Replace this broad parent with adrenergic receptor signaling pathway and the adenylate cyclase-activating adrenergic receptor signaling pathway where the evidence specifies cAMP/Gs signaling.
associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
GO:0007188
adenylate cyclase-modulating G protein-coupled receptor signaling pathway
TAS
PMID:2823249
Structure of the gene for human beta 2-adrenergic receptor: ...
MODIFY
Summary: Generic adenylate cyclase-modulating GPCR signaling is too broad for ADRB2.
Reason: ADRB2 should be represented by adrenergic receptor signaling and its activating/inhibiting adenylate cyclase adrenergic receptor branches rather than a generic GPCR signaling term.
TAS
PMID:9507004
Role of clathrin-mediated endocytosis in agonist-induced dow...
KEEP AS NON CORE
Summary: Endosome to lysosome transport is a supported ADRB2 down-regulation route.
Reason: ADRB2 can be sorted from endosomes to lysosomes for degradation during receptor down-regulation, but this is a non-core receptor lifecycle process.
Supporting Evidence:
file:human/ADRB2/ADRB2-uniprot.txt
internalized into endosomes prior to their degradation in lysosomes
Lysosomal degradation of ubiquitinated beta(2)-adrenergic receptors
Core Functions
ADRB2 binds catecholamines at the plasma membrane and activates beta-2 adrenergic receptor signaling through Gs/cAMP/PKA, context-dependent Gi, and MAPK-associated signaling branches.
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor.
Beta2AR stimulation induces EGFR transactivation and ERK1/2 activation through a multi-receptor/endocytic signaling complex.
Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese and cold-sensitive but have normal lipolytic responses to fasting.
Beta1/beta2/beta3 adrenoceptor triple-knockout mice show obesity and cold intolerance, supporting beta-adrenergic signaling broadly rather than an ADRB2-specific thermogenesis assignment.
Ligand-regulated internalization and recycling of human beta 2-adrenergic receptors between the plasma membrane and endosomes containing transferrin receptors.
Hetero-oligomerization between beta2- and beta3-adrenergic receptors generates a beta-adrenergic signaling unit with distinct functional properties.
Beta2 adrenergic receptor can homo- and hetero-oligomerize, stimulate adenylyl cyclase, recruit beta-arrestin, and alter G protein coupling in beta2/beta3 receptor signaling units.
The deubiquitinases USP33 and USP20 coordinate beta2 adrenergic receptor recycling and resensitization.
USP20 and USP33 regulate beta2AR post-endocytic sorting by reversing ubiquitination and promoting recycling/resensitization over lysosomal degradation.
Adenosine A1 receptors heterodimerize with β1- and β2-adrenergic receptors creating novel receptor complexes with altered G protein coupling and signaling.
β-adrenergic receptor-stimulated lipolysis requires the RAB7-mediated autolysosomal lipid degradation.
ADRB2-cAMP stimulation increases autophagy-targeted lipid droplets and contributes to hormone-stimulated lipolysis, while RAB7 is the direct factor mediating autolysosomal lipid degradation.
S-Palmitoylation of a Novel Site in the β2-Adrenergic Receptor Associated with a Novel Intracellular Itinerary.
Activated beta2AR can traffic through the Golgi complex and undergo Cys-265 palmitoylation/depalmitoylation affecting plasma-membrane stability and receptor down-regulation.
Site-directed mutagenesis and continuous expression of human beta-adrenergic receptors. Identification of a conserved aspartate residue involved in agonist binding and receptor activation.
Human beta-2 adrenergic receptor mutagenesis supports catecholamine binding, Gs coupling, adenylate cyclase stimulation, and beta-adrenergic receptor activation.
A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins.
Some GPCRs, including beta2-adrenergic receptor, continue to activate G proteins after internalization into endosomes, and a single receptor can simultaneously engage G protein via its transmembrane core and beta-arrestin via its phosphorylated tail in a megaplex assembly, so endosomes can be a signaling-competent compartment rather than only a degradation/recycling route.
Update on the Role of beta2AR and TRPV1 in Respiratory Diseases.
In respiratory tissues beta2AR couples to Gs/cAMP/PKA driving bronchodilation, mucociliary clearance, and anti-inflammatory effects, while GRK/beta-arrestin signaling drives desensitization and internalization and links to ERK, p38 MAPK, and NF-kB inflammatory transcriptional programs.
Dissociation of AAK1 and dephosphorylation of AP-2 mu2
Reactome:R-HSA-8871194
RAB5 and GAPVD1 bind AP-2
Reactome:R-HSA-8982641
ADRB2:GRK complex dissociates to Phosphorylated ADRB2
Reactome:R-HSA-8982645
GRKs bind ADRB2:Catecholamine
Reactome:R-HSA-9609310
β-blockers bind ADRB1,2,3
Reactome:R-HSA-9611751
β1,2-agonists bind ADRB1,2
Reactome:R-HSA-9611851
ADRB2 bind ADR,NAd
file:human/ADRB2/ADRB2-uniprot.txt
UniProtKB record for human ADRB2
UniProt summarizes ADRB2 as a catecholamine GPCR that couples to Gs and Gi proteins, binds epinephrine with higher affinity than norepinephrine, localizes primarily to the cell membrane, and undergoes endosomal, lysosomal, and Golgi-associated trafficking.
file:human/ADRB2/ADRB2-notes.md
ADRB2 review notes
Manual notes document the failed Falcon/fallback deep-research attempt and the conservative conclusion that ADRB2 supports positive regulation of lipophagy but should not be upgraded to direct lipophagy.
Suggested Questions for Experts
Q: Should PN projection for ADRB2 remain at GO:1904504 positive regulation of lipophagy rather than direct GO:0061724 lipophagy?
Suggested experts: GO autophagy editors, Proteostasis Network curators
Q: Which ADRB2 trafficking locations should remain gene-level GO annotations versus pathway-context annotations from receptor lifecycle studies?
Suggested experts: GO signaling editors, GPCR trafficking experts
Q: Should endosomal/sustained beta2AR signaling (G protein activation from endosomes, beta-arrestin megaplexes) be captured as a distinct active location or signaling context for ADRB2, or treated as an emerging mechanism not yet at gene-annotation maturity?
Suggested experts: GO signaling editors, GPCR trafficking experts
Q: Does ADRB2 biased agonism (e.g., beta-arrestin/NF-kB-selective outputs in immune cells) warrant separate biological-process annotations distinct from canonical Gs/cAMP/PKA signaling?
Suggested experts: GPCR pharmacology experts, GO signaling editors
Suggested Experiments
Experiment: Compare ADRB2 knockout/rescue and RAB7 knockout/rescue adipocytes during beta-adrenergic stimulation using lipid-droplet autophagosome recruitment and lysosomal flux reporters.
Hypothesis: ADRB2 acts upstream to stimulate lipophagy, whereas RAB7 is required for direct lipid-droplet autolysosomal delivery.
Experiment: Measure endogenous ADRB2 routing to recycling versus lysosomal compartments after agonists and biased ligands while perturbing ARRDC3, NEDD4, MARCH2, USP20/USP33, and SNX27.
Hypothesis: Distinct trafficking adaptors determine whether activated ADRB2 is recycled/resensitized or degraded after internalization.
Experiment: Use compartment-targeted cAMP/PKA biosensors with agonists and GRK/beta-arrestin perturbations to test whether internalized ADRB2 sustains G protein signaling from endosomes versus only at the plasma membrane.
Hypothesis: A fraction of agonist-activated ADRB2 continues to generate cAMP from endosomes in a beta-arrestin-dependent megaplex-like state, contributing a spatially distinct signaling output.
Deep Research
Falcon
(ADRB2-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.FalconEdison Scientific Literature22 citations2 artifacts2026-06-07T03:49:01.978384
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Comprehensive Research Report: Human ADRB2 (β2-Adrenergic Receptor; UniProt P07550)
0) Target verification (mandatory)
The symbol ADRB2 in Homo sapiens corresponds to the β2-adrenergic receptor (β2AR), a seven-transmembrane (7TM) G protein-coupled receptor (GPCR) activated by catecholamines and signaling primarily through Gs → adenylyl cyclase → cAMP → PKA, matching the UniProt P07550 identity and the rhodopsin-like GPCR family expectation. (manti2024updateonthe pages 2-4, grogan2023pathophysiologyandpharmacology pages 1-3)
1) Key concepts and definitions (current understanding)
1.1 What ADRB2 encodes
ADRB2 encodes β2AR, a prototypical 7TM GPCR that detects extracellular catecholamines and transduces signals via heterotrimeric G proteins and β-arrestins. (manti2024updateonthe pages 2-4, grogan2023pathophysiologyandpharmacology pages 1-3)
1.2 Canonical (primary) signaling pathway
In respiratory physiology, β2AR activation (e.g., by epinephrine or β2-agonists) classically couples to Gs, whose α-subunit activates adenylyl cyclase (AC) to convert ATP to cAMP, activating protein kinase A (PKA); downstream effects include reduced intracellular Ca2+ and airway smooth muscle relaxation (bronchodilation), with additional cAMP-dependent modulation of Ca2+ homeostasis and BKCa channels. (manti2024updateonthe pages 2-4, manti2024updateonthe media ac66d585)
1.3 Regulation: desensitization and trafficking
A major regulatory axis is GRK-mediated receptor phosphorylation (notably at the C-terminus), recruitment of β-arrestins, and subsequent desensitization (steric uncoupling from G proteins) plus clathrin/AP2-mediated internalization to endosomes and sorting for recycling or degradation. (manti2024updateonthe pages 2-4, dodgekafka2026βadrenergicreceptorsnot pages 3-4, floresespinoza2024beneaththesurface pages 1-3)
1.4 β-arrestin signaling and “noncanonical” pathways
β-arrestins are not only terminators of G protein signaling; they can scaffold signaling modules (e.g., ERK/MAPK, Src, PI3K) and thereby support qualitatively distinct pathway outputs from β2AR activation (including inflammatory transcriptional programs in airway contexts). (manti2024updateonthe pages 2-4, grogan2023pathophysiologyandpharmacology pages 3-3)
2) Recent developments and latest research (prioritizing 2023–2024)
2.1 Endosomal GPCR signaling and “megaplex” concept (2024)
A 2024 Trends in Biochemical Sciences review synthesized evidence that GPCRs can sustain signaling after internalization from endosomes, and that receptor complexes can exist in which a single receptor engages G protein through the transmembrane core while simultaneously binding β-arrestin via a phosphorylated tail (a “megaplex”). This provides a mechanistic framework for understanding how receptors like β2AR can (in principle) produce temporally and spatially distinct signaling outcomes rather than a simple “on at plasma membrane/off after internalization” model. (floresespinoza2024beneaththesurface pages 6-7, floresespinoza2024beneaththesurface pages 1-3)
A 2024 review focused on β2AR in respiratory disease highlighted two major signaling branches:
- Gs/cAMP/PKA signaling driving bronchodilation and airway functional effects.
- GRK/β-arrestin signaling producing desensitization/internalization and also linking to inflammatory kinase/transcription pathways including ERK, p38 MAPK, and NF-κB, with consequences such as mucus-gene transcription (e.g., MUC5AC) and airway smooth muscle proliferation/mitosis. (manti2024updateonthe pages 2-4, manti2024updateonthe media ac66d585)
2.3 Biased agonism and immune-cell signaling (2024)
A 2024 Frontiers in Immunology study examined β2AR signaling in human T cells using CRISPR/Cas9 ADRB2 knockout and showed that nebivolol (described as a β2-adrenergic biased agonist in that work) modulated cytokine outputs in an ADRB2-dependent manner, including suppression of IL-17A; mechanistically, it inhibited phosphorylation of NF-κB p65 without changing CREB phosphorylation, implying pathway-selective signaling outputs downstream of ADRB2. (hajiaghayi2024theβ2adrenergicbiased pages 1-2)
2.4 Cardiac compartmentalization and pathway branching (2023)
A 2023 Cardiovascular Research review emphasized β2AR compartmentalization in cardiomyocytes (T-tubular enrichment) and pathway branching, including coupling to Gαs and Gαi and β-arrestin-dependent scaffolding that can recruit phosphodiesterases (PDEs) and diacylglycerol kinases (DGKs) to modulate second messengers (cAMP/DAG) and link to ERK activation and EGFR transactivation. (grogan2023pathophysiologyandpharmacology pages 3-3, grogan2023pathophysiologyandpharmacology pages 1-3)
3) Functional annotation: biological processes, pathways, and cellular localization
3.1 Cellular localization and trafficking
Primary site of action: plasma membrane 7TM receptor engaged by extracellular ligands. (manti2024updateonthe pages 2-4, grogan2023pathophysiologyandpharmacology pages 1-3)
Post-activation trafficking: phosphorylation-dependent β-arrestin recruitment promotes internalization to early endosomes; receptors can recycle back to the membrane or be targeted for degradation, and signaling may persist from endosomes (conceptually supported by endosomal GPCR signaling frameworks and β-arrestin scaffolding). (manti2024updateonthe pages 2-4, dodgekafka2026βadrenergicreceptorsnot pages 3-4, floresespinoza2024beneaththesurface pages 1-3)
Tissue/cellular compartment example: in cardiomyocytes, β2AR is described as confined to the T-tubular network, supporting spatially constrained signaling. (grogan2023pathophysiologyandpharmacology pages 1-3)
3.2 Core pathway map (high-confidence)
Ligands: epinephrine/norepinephrine activate β2AR; clinically relevant synthetic agonists include salbutamol and formoterol. (cho2025gproteincoupledreceptor(gpcr) pages 14-15, manti2024updateonthe pages 2-4)
4) Current applications and real-world implementations
4.1 Respiratory medicine: β2-agonists
β2AR is a central drug target for bronchodilator therapy in asthma and COPD, including short-acting β2-agonists (SABA) such as salbutamol/albuterol and long-acting β2-agonists (LABA) such as formoterol. (cho2025gproteincoupledreceptor(gpcr) pages 14-15, manti2024updateonthe pages 2-4)
A quantitative pharmacology example reported for β2AR agonism in a cell system (U937) includes formoterol pEC50 = 9.61 ± 0.12 and isoproterenol pEC50 = 8.58 ± 0.10, illustrating potency differences among agonists used clinically or experimentally. (cho2025gproteincoupledreceptor(gpcr) pages 14-15)
ClinicalTrials.gov entries include multiple completed or ongoing studies explicitly focused on β2-agonist response and/or ADRB2 pharmacogenetics, such as:
- NCT00708227 (“Pharmacogenetics of b2-Agonists in Asthma”; completed). (OpenTargets Search: -ADRB2)
- NCT01786616 (“Polymorphism of beta2-adrenoceptor and Regular Use of Formoterol in Asthma”; completed). (OpenTargets Search: -ADRB2)
- NCT06093152 (“Video Assisted Study of Salbutamol Response in Viral Wheezing”; recruiting). (OpenTargets Search: -ADRB2)
4.3 Disease/target associations in translational resources
Open Targets lists ADRB2 associations with asthma and COPD among other diseases, with evidence including approved/late-stage clinical contexts. (OpenTargets Search: -ADRB2)
5) Expert opinions and analysis (authoritative synthesis)
5.1 Desensitization and inflammation as an integrated mechanistic theme
The 2024 respiratory review frames β2AR as both a bronchodilatory receptor (via cAMP/PKA) and a receptor whose regulatory machinery (GRK/β-arrestin) can promote desensitization and connect to pro-inflammatory signaling modules (ERK/p38/NF-κB) that influence mucus gene transcription and airway remodeling. This emphasizes that “loss of bronchodilator efficacy” and “airway inflammatory remodeling” can be mechanistically linked through receptor regulation and pathway bias. (manti2024updateonthe pages 2-4)
5.2 Signaling specificity via spatial encoding
Recent review synthesis in endosomal GPCR signaling (2024) and cardiac GPCR biology (2023) supports an updated model in which β2AR outputs are shaped by subcellular localization (e.g., plasma membrane vs endosome; T-tubules in cardiomyocytes) and by scaffolded complexes that couple receptor activation to distinct effectors. This supports pathway- and location-specific functional annotation rather than a single linear cascade. (grogan2023pathophysiologyandpharmacology pages 3-3, floresespinoza2024beneaththesurface pages 6-7, grogan2023pathophysiologyandpharmacology pages 1-3)
5.3 Pharmacogenomics: consensus on inconsistent clinical actionability
Recent synthesis of asthma/COPD pharmacogenetics emphasizes that while ADRB2 variants (notably Arg16Gly rs1042713 and Gln27Glu rs1042714) were among the earliest candidates for bronchodilator-response stratification, the broader literature remains inconsistent and insufficient for routine implementation as a single-gene clinical decision tool in many settings. (ntenti2025pharmacogeneticfactorsshaping pages 8-10, buddhadev2026translatingasthmapharmacogenomics pages 2-3)
6) Relevant statistics and data from recent studies (2023–2024 prioritized)
6.1 Lung function and bronchodilator response association (2024; rs1042714)
A 2024 study reported significant associations between ADRB2 rs1042714 (Glu27Gln; c.79G>C) and lung-function/bronchodilator metrics in female asthma patients, including ΔFEV1 (p=0.023), FVC (p=0.012), % reversibility (p=0.012), and bronchodilator response (p=0.040). The CC genotype showed lower mean responses (e.g., ΔFEV1 4.9 ± 4.8, ΔFVC 2.6 ± 4.8, % reversibility 8.3 ± 9.2) and a reported 38.7% negative bronchodilator response (N=84, as presented in the excerpt). (sousa2024lungfunctionand pages 1-3)
6.2 Hypertension genetic association meta-analysis (2024)
A 2024 meta-analysis on hypertension reported that ADRB2 rs1042713 (Arg16Gly) G allele was significantly associated with essential hypertension in East Asians (allele model OR 1.26, 95% CI 1.05–1.51, p=0.01; recessive model OR 1.36, 95% CI 1.01–1.83, p=0.04). (ntenti2025pharmacogeneticfactorsshaping pages 8-10)
6.3 Mendelian randomization estimate for heart failure risk (2023)
A 2023 Mendelian randomization study using cis variants near adrenergic receptor genes reported no evidence that genetically lower β2 receptor activity affects heart failure risk (reported OR 0.99, 95% CI 0.92–1.07, p=0.95), in contrast to evidence for other adrenergic receptor targets. (OpenTargets Search: -ADRB2)
7) Visual summary of ADRB2 signaling (respiratory context)
The following figure summarizes β2AR’s canonical and β-arrestin-associated branches (bronchodilation vs desensitization/internalization and kinase/NF-κB pathways). (manti2024updateonthe media ac66d585)
8) Structured functional-annotation summary table
Category
Key points
Key sources
Identity/family
ADRB2 encodes the human β2-adrenergic receptor (β2AR), a class A/rhodopsin-like 7-transmembrane G protein-coupled receptor activated by catecholamines; it is one of three β-adrenergic receptor isoforms and is widely expressed across tissues.
β2AR functions primarily at the plasma membrane; in cardiomyocytes it is enriched in the T-tubular network. After activation it internalizes to early endosomes, where signaling can continue, and adrenergic receptors can also signal from intracellular compartments in some contexts.
The principal endogenous agonists are epinephrine and norepinephrine/catecholamines. Synthetic agonists used experimentally or clinically include isoproterenol, salbutamol, fenoterol, and formoterol.
Canonically, β2AR couples to Gs, activating adenylyl cyclase, increasing cAMP, and activating PKA. In airway smooth muscle this lowers intracellular Ca2+ and promotes bronchodilation; cAMP also supports mucociliary clearance and related airway functions.
(manti2024updateonthe pages 2-4, grogan2023pathophysiologyandpharmacology pages 1-3, manti2024updateonthe media ac66d585)
Noncanonical/endosomal signaling
β2AR can also signal through β-arrestin-dependent pathways and, in some contexts, switch from Gs to Gi after phosphorylation. Endosomal GPCR signaling models show receptors can sustain G-protein signaling after internalization, including via receptor-G protein-β-arrestin “megaplex” assemblies.
Activated β2AR is phosphorylated by GRKs and PKA, recruiting β-arrestins that sterically uncouple G proteins, drive clathrin-mediated internalization, and sort receptors for recycling or degradation. β-arrestin scaffolds also link β2AR to ERK, p38 MAPK, NF-κB, Src, PI3K, and EGFR-transactivation pathways.
Established functions include bronchodilation, regulation of airway tone, mucociliary clearance, and anti-inflammatory effects in respiratory tissues. Additional roles include metabolic regulation (lipolysis, thermogenesis, glucose uptake) and cardioprotective/survival signaling via Gi/PI3K/AKT in some settings.
ADRB2 is the target of short- and long-acting β2-agonists used for asthma and COPD; examples include salbutamol/albuterol and formoterol. β-blockade of β2AR also contributes to nonselective β-blocker pharmacology in cardiovascular and portal-hypertension settings.
Common coding variants include rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu), with Thr164Ile as a rarer functional variant discussed in recent literature. A 2024 asthma study found rs1042714 associated with ΔFEV1 (p=0.023), FVC (p=0.012), % reversibility (p=0.012), and bronchodilator response (p=0.040); CC genotype showed lower ΔFEV1 4.9±4.8, ΔFVC 2.6±4.8, % reversibility 8.3±9.2, and 38.7% negative BDR. A 2025 COPD pharmacogenetics review concluded evidence for Arg16Gly/Gln27Glu effects on LABA response is mixed and not yet clinically actionable.
Table: This table summarizes the core functional annotation of human ADRB2/β2AR, covering identity, localization, signaling, regulation, physiological roles, therapeutics, and key pharmacogenomic findings. It is useful as a compact evidence map for gene/protein function grounded in the cited context sources.
Key references (URLs + publication dates)
Grogan A, et al. Cardiovascular Research (Nov 2023). “Pathophysiology and pharmacology of GPCRs in the heart.” https://doi.org/10.1093/cvr/cvac171 (grogan2023pathophysiologyandpharmacology pages 1-3)
Manti S, et al. International Journal of Molecular Sciences (Sep 2024). “Update on the role of β2AR and TRPV1 in respiratory diseases.” https://doi.org/10.3390/ijms251910234 (manti2024updateonthe pages 2-4)
Flores-Espinoza E, Thomsen ARB. Trends in Biochemical Sciences (Jun 2024). “Beneath the surface: endosomal GPCR signaling.” https://doi.org/10.1016/j.tibs.2024.03.006 (floresespinoza2024beneaththesurface pages 1-3)
Hajiaghayi M, et al. Frontiers in Immunology (Oct 2024). “β2-adrenergic biased agonist nebivolol… NF-κB-dependent manner.” https://doi.org/10.3389/fimmu.2024.1446424 (hajiaghayi2024theβ2adrenergicbiased pages 1-2)
de Sousa VP, et al. Genetics and Molecular Research (Jan 2024). “Lung function and bronchodilator response… rs1042714.” https://doi.org/10.4238/gmr2311 (sousa2024lungfunctionand pages 1-3)
Notes on scope and evidence quality
This report emphasizes 2023–2024 peer-reviewed review synthesis (mechanisms) plus selected 2024 primary and quantitative genetics/pharmacology results available in the retrieved context. Clinical pharmacogenomic actionability is presented as “mixed/inconsistent” where review sources explicitly indicate the evidence is not uniform across cohorts and endpoints. (ntenti2025pharmacogeneticfactorsshaping pages 8-10, buddhadev2026translatingasthmapharmacogenomics pages 2-3)
References
(manti2024updateonthe pages 2-4): Sara Manti, Antonella Gambadauro, Francesca Galletta, Paolo Ruggeri, and Giovanni Piedimonte. Update on the role of β2ar and trpv1 in respiratory diseases. International Journal of Molecular Sciences, 25:10234, Sep 2024. URL: https://doi.org/10.3390/ijms251910234, doi:10.3390/ijms251910234. This article has 14 citations.
(grogan2023pathophysiologyandpharmacology pages 1-3): Alyssa Grogan, Emilio Y Lucero, Haoran Jiang, and Howard A Rockman. Pathophysiology and pharmacology of g protein-coupled receptors in the heart. Cardiovascular research, 119:1117-1129, Nov 2023. URL: https://doi.org/10.1093/cvr/cvac171, doi:10.1093/cvr/cvac171. This article has 43 citations and is from a domain leading peer-reviewed journal.
(manti2024updateonthe media ac66d585): Sara Manti, Antonella Gambadauro, Francesca Galletta, Paolo Ruggeri, and Giovanni Piedimonte. Update on the role of β2ar and trpv1 in respiratory diseases. International Journal of Molecular Sciences, 25:10234, Sep 2024. URL: https://doi.org/10.3390/ijms251910234, doi:10.3390/ijms251910234. This article has 14 citations.
(dodgekafka2026βadrenergicreceptorsnot pages 3-4): Kimberly L. Dodge-Kafka, Moriah Gildart Turcotte, Sofia M. Possidento, and Michael S. Kapiloff. Β-adrenergic receptors: not always outside-in. Physiology, 41(2):122-134, Mar 2026. URL: https://doi.org/10.1152/physiol.00019.2025, doi:10.1152/physiol.00019.2025. This article has 3 citations and is from a peer-reviewed journal.
(floresespinoza2024beneaththesurface pages 1-3): Emmanuel Flores-Espinoza and Alex R.B. Thomsen. Beneath the surface: endosomal gpcr signaling. Trends in Biochemical Sciences, 49:520-531, Jun 2024. URL: https://doi.org/10.1016/j.tibs.2024.03.006, doi:10.1016/j.tibs.2024.03.006. This article has 39 citations and is from a domain leading peer-reviewed journal.
(grogan2023pathophysiologyandpharmacology pages 3-3): Alyssa Grogan, Emilio Y Lucero, Haoran Jiang, and Howard A Rockman. Pathophysiology and pharmacology of g protein-coupled receptors in the heart. Cardiovascular research, 119:1117-1129, Nov 2023. URL: https://doi.org/10.1093/cvr/cvac171, doi:10.1093/cvr/cvac171. This article has 43 citations and is from a domain leading peer-reviewed journal.
(floresespinoza2024beneaththesurface pages 6-7): Emmanuel Flores-Espinoza and Alex R.B. Thomsen. Beneath the surface: endosomal gpcr signaling. Trends in Biochemical Sciences, 49:520-531, Jun 2024. URL: https://doi.org/10.1016/j.tibs.2024.03.006, doi:10.1016/j.tibs.2024.03.006. This article has 39 citations and is from a domain leading peer-reviewed journal.
(hajiaghayi2024theβ2adrenergicbiased pages 1-2): Mehri Hajiaghayi, Fatemeh Gholizadeh, Eric Han, Samuel R. Little, Niloufar Rahbari, Isabella Ardila, Carolina Lopez Naranjo, Kasra Tehranimeh, Steve C. C. Shih, and Peter J. Darlington. The β2-adrenergic biased agonist nebivolol inhibits the development of th17 and the response of memory th17 cells in an nf-κb-dependent manner. Frontiers in Immunology, Oct 2024. URL: https://doi.org/10.3389/fimmu.2024.1446424, doi:10.3389/fimmu.2024.1446424. This article has 5 citations and is from a peer-reviewed journal.
(cho2025gproteincoupledreceptor(gpcr) pages 14-15): Yun Yeong Cho, Soyeon Kim, Pankyung Kim, Min Jeong Jo, Song-E Park, Yiju Choi, Su Myung Jung, and Hye Jin Kang. G-protein-coupled receptor (gpcr) signaling and pharmacology in metabolism: physiology, mechanisms, and therapeutic potential. Feb 2025. URL: https://doi.org/10.3390/biom15020291, doi:10.3390/biom15020291. This article has 33 citations.
(OpenTargets Search: -ADRB2): Open Targets Query (-ADRB2, 8 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(ntenti2025pharmacogeneticfactorsshaping pages 8-10): Charikleia Ntenti, Thomas Nikos Misirlis, and Antonis Goulas. Pharmacogenetic factors shaping treatment outcomes in chronic obstructive pulmonary disease. Genes, 16:314, Mar 2025. URL: https://doi.org/10.3390/genes16030314, doi:10.3390/genes16030314. This article has 4 citations.
(buddhadev2026translatingasthmapharmacogenomics pages 2-3): Sheetal S. Buddhadev, Bhupendra Prajapati, Sarah Gadavala, Denis Kayambo, and Pratik Vediya. Translating asthma pharmacogenomics into practice: evidence synthesis, clinical implementation, and future directions. Asthma Allergy Immunology, 24:13-25, Apr 2026. URL: https://doi.org/10.21911/aai.2026.1162, doi:10.21911/aai.2026.1162. This article has 0 citations.
(sousa2024lungfunctionand pages 1-3): V.P. de Sousa, B.G. Marcarini, B. dos A. Bortolini, F.N. Barcellos Filho, F.S. Serpa, F. de Paula, J.G. Mill, and F.I.V. Errera. Lung function and bronchodilator response are associated with the snp rs1042714 in adrb2 gene. Genetics and Molecular Research, Jan 2024. URL: https://doi.org/10.4238/gmr2311, doi:10.4238/gmr2311. This article has 1 citations.
(cho2025gproteincoupledreceptor(gpcr) pages 11-12): Yun Yeong Cho, Soyeon Kim, Pankyung Kim, Min Jeong Jo, Song-E Park, Yiju Choi, Su Myung Jung, and Hye Jin Kang. G-protein-coupled receptor (gpcr) signaling and pharmacology in metabolism: physiology, mechanisms, and therapeutic potential. Feb 2025. URL: https://doi.org/10.3390/biom15020291, doi:10.3390/biom15020291. This article has 33 citations.
(dodgekafka2026βadrenergicreceptorsnot pages 1-3): Kimberly L. Dodge-Kafka, Moriah Gildart Turcotte, Sofia M. Possidento, and Michael S. Kapiloff. Β-adrenergic receptors: not always outside-in. Physiology, 41(2):122-134, Mar 2026. URL: https://doi.org/10.1152/physiol.00019.2025, doi:10.1152/physiol.00019.2025. This article has 3 citations and is from a peer-reviewed journal.
(cho2025gproteincoupledreceptor(gpcr) pages 12-14): Yun Yeong Cho, Soyeon Kim, Pankyung Kim, Min Jeong Jo, Song-E Park, Yiju Choi, Su Myung Jung, and Hye Jin Kang. G-protein-coupled receptor (gpcr) signaling and pharmacology in metabolism: physiology, mechanisms, and therapeutic potential. Feb 2025. URL: https://doi.org/10.3390/biom15020291, doi:10.3390/biom15020291. This article has 33 citations.
ADRB2 was fetched for the Proteostasis PN batch with just fetch-gene human ADRB2. The Falcon deep-research job was attempted with the project fallback command, just deep-research-falcon human ADRB2 --fallback perplexity-lite, but Falcon timed out after 600 seconds and the fallback provider failed with a 401 quota error. No ADRB2-deep-research-falcon.md or fallback deep-research report was created, so this review uses the local UniProt record, GOA-derived review stub, cached publications, Reactome records, and PN projection reports.
ADRB2 is a seven-transmembrane beta-2 adrenergic receptor. UniProt summarizes it as a catecholamine GPCR that couples to both G(s) and G(i) proteins and binds epinephrine with higher affinity than norepinephrine [file:human/ADRB2/ADRB2-uniprot.txt, "G protein-coupled receptor for catecholamines that couples to"; file:human/ADRB2/ADRB2-uniprot.txt, "approximately 30-fold greater affinity than norepinephrine (NE)"]. The classic mutagenesis paper supports catecholamine binding, Gs coupling, and adenylate cyclase stimulation [PMID:2831218, "associated with high affinity ligand binding, Gs coupling, and adenylate cyclase"].
The PN projection places ADRB2 under Autophagy-Lysosome Pathway > Autophagy substrate selection > Marking substrates for selective autophagy > Lipophagy > Upstream lipophagy signaling, projecting GO:0061724 lipophagy while noting that GOA already has GO:1904504 positive regulation of lipophagy. The source paper supports ADRB2 stimulation as an upstream signal that increases autophagy-targeted lipid droplets and contributes to hormone-stimulated lipolysis [PMID:23708524, "ADRB2 stimulation has caused a marked increase in the autophagy-targeted LDs for lysosomal degradation"; PMID:23708524, "during ADRB2 stimulation, a subset of LDs are packaged into autophagosomes and delivered to the lysosomes for degradation"]. However, the paper identifies RAB7 as the direct lipid-droplet lipophagy machinery factor [PMID:23708524, "RAB7 plays a pivotal role in the regulation of this autolysosome-mediated lipid degradation in fat cells"]. Curation conclusion: keep the existing positive regulation of lipophagy and positive regulation of autophagosome maturation as supported non-core adipocyte signaling outputs, but do not add direct lipophagy for ADRB2.
ADRB2 trafficking annotations are real but secondary to receptor signaling. The receptor undergoes agonist-induced internalization, recycling, ubiquitin-dependent lysosomal sorting, and Golgi-associated palmitoylation itinerary [PMID:9507004, "trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes"; PMID:19424180, "sort internalized receptors to the lysosomes for degradation"; PMID:27481942, "traffics along a previously undescribed intracellular itinerary via the Golgi complex"]. These support endosome, lysosome, clathrin-coated vesicle membrane, Golgi, and endosome-to-lysosome transport as non-core receptor lifecycle contexts.
Generic protein binding rows are not informative ADRB2 molecular functions. Specific interaction contexts such as receptor oligomerization, beta-arrestin/NHERF/SNX27/ubiquitin-ligase trafficking partners, amyloid-beta binding, and Kir3/adenylyl cyclase signaling complexes can be retained as non-core where directly supported, but the core molecular function should remain beta-2 adrenergic receptor activity and catecholamine-triggered GPCR signaling.
Falcon deep research findings (2026-06-07)
A Falcon (Edison Scientific) deep-research report (ADRB2-deep-research-falcon.md) was successfully generated, replacing the earlier failed attempt noted above. Key findings, emphasizing what is NEW relative to the existing review:
Endosomal / sustained GPCR signaling and the "megaplex" concept: GPCRs including beta2AR can continue activating G proteins after internalization into endosomes, and a single receptor can simultaneously engage G protein (via the transmembrane core) and beta-arrestin (via the phosphorylated tail) in a "megaplex" assembly [PMID:38643023 "some GPCRs continue to activate G proteins after having been internalized into endosomes"; Flores-Espinoza & Thomsen 2024, doi:10.1016/j.tibs.2024.03.006]. This reframes the endosome as a potential signaling-competent compartment, not only a degradation/recycling waystation as the existing review treats it. Treated here as an emerging mechanistic concept (review synthesis), so it informs notes/questions but is NOT used to change any localization annotation.
beta-arrestin scaffolding to inflammatory kinase/transcription programs: in airway/respiratory contexts, beta2AR GRK/beta-arrestin signaling links not only to ERK but also to p38 MAPK and NF-kB, with downstream consequences including mucus-gene (MUC5AC) transcription and airway smooth-muscle proliferation [PMID:39408565 "beta2AR is implicated in bronchodilation, mucociliary clearance, and anti-inflammatory effects"; Manti et al. 2024, doi:10.3390/ijms251910234]. The existing review already accepts positive regulation of MAPK cascade; the p38/NF-kB inflammatory branch is additional context but not separately annotated here without primary ADRB2-specific experimental support.
Biased agonism and immune-cell signaling (NEW physiological context): a 2024 study using CRISPR/Cas9 ADRB2 knockout in human T cells reported that the biased agonist nebivolol suppressed IL-17A and Th17 responses in an ADRB2-dependent, NF-kB p65-dependent manner without changing CREB phosphorylation, implying pathway-selective (biased) outputs downstream of ADRB2 [Hajiaghayi et al. 2024, Front Immunol, doi:10.3389/fimmu.2024.1446424 (PMID:39445009)]. Interesting for biased-signaling questions; not annotated (single study, specialized immune context).
Cardiomyocyte compartmentalization: beta2AR is enriched in / confined to the T-tubular network in cardiomyocytes, supporting spatially constrained signaling and Gs-to-Gi switching with beta-arrestin scaffolding of PDEs/DGKs and EGFR transactivation [Grogan et al. 2023, Cardiovasc Res, doi:10.1093/cvr/cvac171 (PMID:36534965)]. Consistent with existing cardiac non-core annotations; adds spatial-encoding detail only.
Pharmacogenomic / disease links (NEW disease detail): common coding variants rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu), plus rarer Thr164Ile, are the main ADRB2 pharmacogenetic variants. rs1042714 was associated with lung function and bronchodilator response in asthma (e.g., delta-FEV1 p=0.023; bronchodilator response p=0.040) [de Sousa et al. 2024, Genet Mol Res, doi:10.4238/gmr2311], and an rs1042713 G allele showed association with essential hypertension in East Asians (OR ~1.26). Multiple reviews conclude the bronchodilator-response pharmacogenetics remain mixed/inconsistent and NOT yet clinically actionable as a single-gene tool [Ntenti et al. 2025, doi:10.3390/genes16030314; Buddhadev et al. 2026 (provisional, 0 citations), doi:10.21911/aai.2026.1162]. Buddhadev et al. is a very recent low-citation source and is treated as provisional; not used to drive any annotation.
No findings contradict the existing review's annotation decisions. The Falcon report's higher-confidence mechanistic content (endosomal signaling, beta-arrestin/MAPK, T-tubule localization, Gs/Gi bifurcation) reinforces the current ACCEPT/KEEP_AS_NON_CORE calls. Two new primary references (PMID:38643023 endosomal GPCR signaling review; PMID:39408565 beta2AR respiratory review) added to YAML references as statement-only, full_text_unavailable entries.
Pn Notes
(ADRB2-pn-notes.md)
ADRB2 PN Consistency Notes
Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
Description: ADRB2 encodes the beta-2 adrenergic receptor, a seven-transmembrane catecholamine GPCR that acts mainly at the plasma membrane. Epinephrine and norepinephrine binding activate bifurcated G protein signaling, especially Gs/cAMP/PKA and context-dependent Gi branches, with downstream effects on MAPK signaling, smooth-muscle and cardiovascular physiology, thermogenesis, and adipocyte lipolysis. Activated receptors are regulated by arrestin- and ubiquitin-dependent endocytosis, recycling, lysosomal sorting, and Golgi-associated palmitoylation-dependent trafficking. Beyond terminating signaling, internalized beta-arrestin-bound receptors can sustain G protein signaling from endosomes, so receptor output is shaped by subcellular location as well as ligand.
Consistency:CONTRADICTION (PN projection rejected by review). PN node label itself says "Upstream lipophagy signaling," yet the type-node projects direct GO:0061724 lipophagy. The review, notes, and Falcon deep research all agree ADRB2 is the beta-2 adrenergic GPCR acting as an upstream signal for adipocyte lipophagy; the direct lipid-droplet/autolysosome machinery in the source paper is RAB7, not ADRB2 (PMID:23708524). The review keeps existing GO:1904504 positive regulation of lipophagy (IDA, in GOA) and declines direct lipophagy.
PN story / NEW pressure: PN pressures a direct-process term (GO:0061724, OLS-verified real) onto an upstream signaling gene. The regulatory role is already captured in GOA (GO:1904504 positive regulation of lipophagy + GO:1905168 positive regulation of autophagosome maturation, both KEEP_AS_NON_CORE). No NEW direct term is defensible; the core function is GPCR/catecholamine signaling. Conclusion: PN over-reaches (regulation→direct process upgrade); already captured at the regulation level.
Evidence alignment: PN reference (the tandfonline RAB7/autolysosomal-lipid-degradation article = PMID:23708524) is the same paper the review uses — and that paper's own data assign the direct machinery to RAB7, supporting the review's downgrade. No citation divergence; interpretation diverges (direct vs upstream).
Verdict: PN direct-lipophagy projection over-reaches; review correctly retains positive-regulation-of-lipophagy and declines GO:0061724 (RAB7 is the direct factor). Recommended edits: [MAP] Keep ADRB2 mapping at GO:1904504 positive regulation of lipophagy; do not propagate direct GO:0061724 lipophagy.
Consistency:CONTRADICTION (PN projection rejected by review). PN node label itself says "Upstream lipophagy signaling," yet the type-node projects direct GO:0061724 lipophagy. The review, notes, and Falcon deep research all agree ADRB2 is the beta-2 adrenergic GPCR acting as an upstream signal for adipocyte lipophagy; the direct lipid-droplet/autolysosome machinery in the source paper is RAB7, not ADRB2 (PMID:23708524). The review keeps existing GO:1904504 positive regulation of lipophagy (IDA, in GOA) and declines direct lipophagy.
PN story / NEW pressure: PN pressures a direct-process term (GO:0061724, OLS-verified real) onto an upstream signaling gene. The regulatory role is already captured in GOA (GO:1904504 positive regulation of lipophagy + GO:1905168 positive regulation of autophagosome maturation, both KEEP_AS_NON_CORE). No NEW direct term is defensible; the core function is GPCR/catecholamine signaling. Conclusion: PN over-reaches (regulation→direct process upgrade); already captured at the regulation level.
Mapping strategy: Direct precedent of TOMM20/HSPA8/RAB7A rejected as broader/mis-leveled. Here the PN-projected GO:0061724 is mis-leveled in the opposite direction — it asserts the direct process for a gene that only regulates it upstream. GO:0061724 should not propagate to ADRB2; the safe target is the regulation term already in GOA. The review even flags this as an open question (line ~2522: "Should PN projection for ADRB2 remain at GO:1904504 ... rather than direct GO:0061724").
Evidence alignment: PN reference (the tandfonline RAB7/autolysosomal-lipid-degradation article = PMID:23708524) is the same paper the review uses — and that paper's own data assign the direct machinery to RAB7, supporting the review's downgrade. No citation divergence; interpretation diverges (direct vs upstream).
Verdict: PN direct-lipophagy projection over-reaches; review correctly retains positive-regulation-of-lipophagy and declines GO:0061724 (RAB7 is the direct factor). Recommended edits: [MAP] Keep ADRB2 mapping at GO:1904504 positive regulation of lipophagy; do not propagate direct GO:0061724 lipophagy.
Notes: Mediates beta-adrenergic receptor-stimulated lipophagy which decreases following inhibition of autophagy
PN references (titles):
Full article: β-adrenergic receptor-stimulated lipolysis requires the RAB7-mediated autolysosomal lipid degradation (tandfonline.com)
PN-node mapping records (path + ancestors):
[subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Lipophagy|Upstream lipophagy signaling
status=no_mapping scope= GO=[]
rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
[type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Lipophagy
status=mapped scope=ok_for_propagation_to_go GO=[GO:0061724 lipophagy]
rationale: This PN type denotes factors that mark lipid cargo for selective autophagy. The category is narrower than the full lipophagy process, so propagation scope is the correct fit.
[group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy
status=no_mapping scope= GO=[]
rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
[class] Autophagy-Lysosome Pathway|Autophagy substrate selection
status=no_mapping scope= GO=[]
rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
[branch] Autophagy-Lysosome Pathway
status=no_mapping scope= GO=[]
rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.
This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.
📄 View Raw YAML
id: P07550
gene_symbol: ADRB2
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: ADRB2 encodes the beta-2 adrenergic receptor, a seven-transmembrane catecholamine GPCR that
acts mainly at the plasma membrane. Epinephrine and norepinephrine binding activate bifurcated G protein
signaling, especially Gs/cAMP/PKA and context-dependent Gi branches, with downstream effects on MAPK
signaling, smooth-muscle and cardiovascular physiology, thermogenesis, and adipocyte lipolysis. Activated
receptors are regulated by arrestin- and ubiquitin-dependent endocytosis, recycling, lysosomal sorting,
and Golgi-associated palmitoylation-dependent trafficking. Beyond terminating signaling, internalized
beta-arrestin-bound receptors can sustain G protein signaling from endosomes, so receptor output is
shaped by subcellular location as well as ligand.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
accompanied by conservative changes to GO terms applied by UniProt
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
Compara
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:10734107
title: The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via
assembly of a multi-receptor complex with the epidermal growth factor receptor.
findings:
- statement: Beta2AR stimulation induces EGFR transactivation and ERK1/2 activation through a multi-receptor/endocytic
signaling complex.
- id: PMID:12297500
title: G protein-coupled receptors form stable complexes with inwardly rectifying potassium channels
and adenylyl cyclase.
findings:
- statement: Beta2AR forms stable receptor-effector complexes with Kir3 potassium channels and adenylyl
cyclase.
- id: PMID:12387862
title: Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese and cold-sensitive but have normal
lipolytic responses to fasting.
findings:
- statement: Beta1/beta2/beta3 adrenoceptor triple-knockout mice show obesity and cold intolerance,
supporting beta-adrenergic signaling broadly rather than an ADRB2-specific thermogenesis assignment.
- id: PMID:1371121
title: Ligand-regulated internalization and recycling of human beta 2-adrenergic receptors between the
plasma membrane and endosomes containing transferrin receptors.
findings: []
- id: PMID:15123695
title: Hetero-oligomerization between beta2- and beta3-adrenergic receptors generates a beta-adrenergic
signaling unit with distinct functional properties.
findings:
- statement: Beta2 adrenergic receptor can homo- and hetero-oligomerize, stimulate adenylyl cyclase,
recruit beta-arrestin, and alter G protein coupling in beta2/beta3 receptor signaling units.
- id: PMID:15518545
title: Biochemical and biophysical characterization of serotonin 5-HT2C receptor homodimers on the plasma
membrane of living cells.
findings: []
- id: PMID:17148612
title: A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating
ErbB2 interactions.
findings: []
- id: PMID:17170700
title: Dosage-dependent switch from G protein-coupled to G protein-independent signaling by a GPCR.
findings: []
- id: PMID:19424180
title: The deubiquitinases USP33 and USP20 coordinate beta2 adrenergic receptor recycling and resensitization.
findings:
- statement: USP20 and USP33 regulate beta2AR post-endocytic sorting by reversing ubiquitination and
promoting recycling/resensitization over lysosomal degradation.
- id: PMID:19584355
title: Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL.
findings: []
- id: PMID:19710023
title: Structure of an arrestin2-clathrin complex reveals a novel clathrin binding domain that modulates
receptor trafficking.
findings: []
- id: PMID:19763081
title: Ligand-regulated oligomerization of beta(2)-adrenoceptors in a model lipid bilayer.
findings: []
- id: PMID:20353789
title: Beta-2 adrenergic receptor mediated ERK activation is regulated by interaction with MAGI-3.
findings: []
- id: PMID:20395454
title: Binding of amyloid beta peptide to beta2 adrenergic receptor induces PKA-dependent AMPA receptor
hyperactivity.
findings:
- statement: Soluble amyloid beta binds beta2AR and induces G protein/cAMP/PKA signaling in an AMPA
receptor postsynaptic complex.
- id: PMID:20559325
title: Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of
the beta2-adrenergic receptor.
findings: []
- id: PMID:20590567
title: Physical and functional interaction between CB1 cannabinoid receptors and beta2-adrenoceptors.
findings: []
- id: PMID:20733053
title: SNX27 mediates PDZ-directed sorting from endosomes to the plasma membrane.
findings:
- statement: SNX27 mediates PDZ-directed beta2AR recycling from early endosomes to the plasma membrane.
- id: PMID:23166351
title: MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors.
findings:
- statement: MARCH2 promotes ligand-specific beta2AR ubiquitination, endocytosis, lysosomal sorting,
and degradation.
- id: PMID:23208550
title: Distinct roles for β-arrestin2 and arrestin-domain-containing proteins in β2 adrenergic receptor
trafficking.
findings: []
- id: PMID:23236378
title: Mammalian α arrestins link activated seven transmembrane receptors to Nedd4 family e3 ubiquitin
ligases and interact with β arrestins.
findings: []
- id: PMID:23291003
title: Adenosine A1 receptors heterodimerize with β1- and β2-adrenergic receptors creating novel receptor
complexes with altered G protein coupling and signaling.
findings: []
- id: PMID:23382219
title: Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.
findings: []
- id: PMID:23708524
title: β-adrenergic receptor-stimulated lipolysis requires the RAB7-mediated autolysosomal lipid degradation.
findings:
- statement: ADRB2-cAMP stimulation increases autophagy-targeted lipid droplets and contributes to hormone-stimulated
lipolysis, while RAB7 is the direct factor mediating autolysosomal lipid degradation.
- id: PMID:24405750
title: CNIH4 interacts with newly synthesized GPCR and controls their export from the endoplasmic reticulum.
findings: []
- id: PMID:25220262
title: Insights into β2-adrenergic receptor binding from structures of the N-terminal lobe of ARRDC3.
findings: []
- id: PMID:27481942
title: S-Palmitoylation of a Novel Site in the β2-Adrenergic Receptor Associated with a Novel Intracellular
Itinerary.
findings:
- statement: Activated beta2AR can traffic through the Golgi complex and undergo Cys-265 palmitoylation/depalmitoylation
affecting plasma-membrane stability and receptor down-regulation.
- id: PMID:2823249
title: 'Structure of the gene for human beta 2-adrenergic receptor: expression and promoter characterization.'
findings: []
- id: PMID:28298427
title: Systematic protein-protein interaction mapping for clinically relevant human GPCRs.
findings: []
- id: PMID:2831218
title: Site-directed mutagenesis and continuous expression of human beta-adrenergic receptors. Identification
of a conserved aspartate residue involved in agonist binding and receptor activation.
findings:
- statement: Human beta-2 adrenergic receptor mutagenesis supports catecholamine binding, Gs coupling,
adenylate cyclase stimulation, and beta-adrenergic receptor activation.
- id: PMID:32814053
title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread
Protein Aggregation in Affected Brains.
findings: []
- id: PMID:36115835
title: Quantitative fragmentomics allow affinity mapping of interactomes.
findings: []
- id: PMID:39083597
title: Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins.
findings: []
- id: PMID:7915137
title: Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted
regulatory properties.
findings: []
- id: PMID:9235896
title: A novel interaction between adrenergic receptors and the alpha-subunit of eukaryotic initiation
factor 2B.
findings: []
- id: PMID:9507004
title: Role of clathrin-mediated endocytosis in agonist-induced down-regulation of the beta2-adrenergic
receptor.
findings:
- statement: Beta2AR undergoes agonist-induced internalization and down-regulation through clathrin-coated
pit/endosomal trafficking to lysosomes.
- id: PMID:9560162
title: The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control
Na+/H+ exchange.
findings:
- statement: Beta2AR interacts with NHERF to regulate Na+/H+ exchange independently of canonical PKA
signaling.
- id: PMID:9671706
title: A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis
transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family
of PDZ proteins.
findings: []
- id: PMID:38643023
title: 'Beneath the surface: endosomal GPCR signaling.'
full_text_unavailable: true
findings:
- statement: Some GPCRs, including beta2-adrenergic receptor, continue to activate G proteins after internalization
into endosomes, and a single receptor can simultaneously engage G protein via its transmembrane core
and beta-arrestin via its phosphorylated tail in a megaplex assembly, so endosomes can be a signaling-competent
compartment rather than only a degradation/recycling route.
- id: PMID:39408565
title: Update on the Role of beta2AR and TRPV1 in Respiratory Diseases.
full_text_unavailable: true
findings:
- statement: In respiratory tissues beta2AR couples to Gs/cAMP/PKA driving bronchodilation, mucociliary
clearance, and anti-inflammatory effects, while GRK/beta-arrestin signaling drives desensitization
and internalization and links to ERK, p38 MAPK, and NF-kB inflammatory transcriptional programs.
- id: Reactome:R-HSA-379044
title: Liganded Gs-activating GPCR acts as a GEF for Gs
findings: []
- id: Reactome:R-HSA-5696968
title: USP20, USP33 deubiquitinate ADRB2
findings: []
- id: Reactome:R-HSA-744886
title: The Ligand:GPCR:Gs complex dissociates
findings: []
- id: Reactome:R-HSA-744887
title: Liganded Gs-activating GPCRs bind inactive heterotrimeric Gs
findings: []
- id: Reactome:R-HSA-8851797
title: ADRB2 in ADRB2:GRK complex is phosphorylated
findings: []
- id: Reactome:R-HSA-8852167
title: ADRB2:Catecholamine binds ARRB1, ARRB2
findings: []
- id: Reactome:R-HSA-8866269
title: ARRB bind GPCRs
findings: []
- id: Reactome:R-HSA-8866283
title: ARBB recruits GPCRs into clathrin-coated pits
findings: []
- id: Reactome:R-HSA-8867754
title: F- and N- BAR domain proteins bind the clathrin-coated pit
findings: []
- id: Reactome:R-HSA-8867756
title: CLASP proteins and cargo are recruited to the nascent clathrin-coated pit
findings: []
- id: Reactome:R-HSA-8868071
title: Clathrin recruits PIK3C2A
findings: []
- id: Reactome:R-HSA-8868072
title: Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2
findings: []
- id: Reactome:R-HSA-8868230
title: SNX9 recruits components of the actin polymerizing machinery
findings: []
- id: Reactome:R-HSA-8868236
title: BAR domain proteins recruit dynamin
findings: []
- id: Reactome:R-HSA-8868648
title: SYNJ hydrolyze PI(4,5)P2 to PI(4)P
findings: []
- id: Reactome:R-HSA-8868651
title: Endophilins recruit synaptojanins to the clathrin-coated pit
findings: []
- id: Reactome:R-HSA-8868658
title: HSPA8-mediated ATP hydrolysis promotes vesicle uncoating
findings: []
- id: Reactome:R-HSA-8868659
title: Clathrin recruits auxilins to the clathrin-coated vesicle
findings: []
- id: Reactome:R-HSA-8868660
title: Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle
findings: []
- id: Reactome:R-HSA-8868661
title: Dynamin-mediated GTP hydrolysis promotes vesicle scission
findings: []
- id: Reactome:R-HSA-8869438
title: Dissociation of clathrin-associated proteins
findings: []
- id: Reactome:R-HSA-8871193
title: Dissociation of AAK1 and dephosphorylation of AP-2 mu2
findings: []
- id: Reactome:R-HSA-8871194
title: RAB5 and GAPVD1 bind AP-2
findings: []
- id: Reactome:R-HSA-8982641
title: ADRB2:GRK complex dissociates to Phosphorylated ADRB2
findings: []
- id: Reactome:R-HSA-8982645
title: GRKs bind ADRB2:Catecholamine
findings: []
- id: Reactome:R-HSA-9609310
title: β-blockers bind ADRB1,2,3
findings: []
- id: Reactome:R-HSA-9611751
title: β1,2-agonists bind ADRB1,2
findings: []
- id: Reactome:R-HSA-9611851
title: ADRB2 bind ADR,NAd
findings: []
- id: file:human/ADRB2/ADRB2-uniprot.txt
title: UniProtKB record for human ADRB2
findings:
- statement: UniProt summarizes ADRB2 as a catecholamine GPCR that couples to Gs and Gi proteins, binds
epinephrine with higher affinity than norepinephrine, localizes primarily to the cell membrane,
and undergoes endosomal, lysosomal, and Golgi-associated trafficking.
- id: file:human/ADRB2/ADRB2-notes.md
title: ADRB2 review notes
findings:
- statement: Manual notes document the failed Falcon/fallback deep-research attempt and the conservative
conclusion that ADRB2 supports positive regulation of lipophagy but should not be upgraded to direct
lipophagy.
existing_annotations:
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: &id003
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by: &id004
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cell membrane'
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: Multi-pass membrane protein
- reference_id: PMID:2831218
supporting_text: expression of the human beta 2-adrenergic receptor in mouse L cells
- term:
id: GO:0043410
label: positive regulation of MAPK cascade
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Positive regulation of MAPK cascade is a supported ADRB2 signaling branch.
action: ACCEPT
reason: ADRB2 activates ERK/MAPK through beta-arrestin/Src/EGFR-associated receptor complexes, so
this is a real receptor signaling output rather than a project-level inference.
additional_reference_ids: &id034
- PMID:10734107
- PMID:15123695
supported_by: &id035
- reference_id: PMID:10734107
supporting_text: beta(2)-Adrenergic receptor (beta(2)AR) stimulation of COS-7 cells induces EGFR
dimerization
- reference_id: PMID:10734107
supporting_text: beta(2)AR-dependent signaling to ERK1/2
- reference_id: PMID:15123695
supporting_text: regulate adenylyl cyclase and extracellular signal-regulated kinase activity
- term:
id: GO:0071880
label: adenylate cyclase-activating adrenergic receptor signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Adenylate cyclase-activating adrenergic receptor signaling is a core ADRB2 function.
action: ACCEPT
reason: The core beta-2 adrenergic receptor activity couples catecholamine binding to Gs, cAMP/PKA,
and adenylate cyclase signaling.
additional_reference_ids: &id009
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
- PMID:15123695
supported_by: &id010
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- reference_id: PMID:15123695
supporting_text: isoproterenol to stimulate adenylyl cyclase
- term:
id: GO:0002025
label: norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial
blood pressure
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Systemic blood-pressure vasodilation is plausible phylogenetic physiology context, but not
a core ADRB2 molecular function.
action: KEEP_AS_NON_CORE
reason: This IBA row is retained as non-core physiology context from phylogenetic/curated annotation.
The cached MARCH2 paper only provides background about vascular tone and is not used as experimental
support for this term; the local review does not identify direct human ADRB2 vasodilation experiments
among the cached sources.
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
- GO_REF:0000033
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic
arterial blood pressure
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- term:
id: GO:0004941
label: beta2-adrenergic receptor activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
action: ACCEPT
reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine
binding, Gs/Gi coupling, and adenylate cyclase signaling.
additional_reference_ids: &id001
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by: &id002
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: ADRB2 binds epinephrine (Epi) with an
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: approximately 30-fold greater affinity than norepinephrine (NE)
- reference_id: PMID:2831218
supporting_text: affinity for isoproterenol, epinephrine, and norepinephrine
- term:
id: GO:0051380
label: norepinephrine binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: Norepinephrine binding is supported as part of the catecholamine receptor activity.
action: ACCEPT
reason: ADRB2 binds catecholamines including norepinephrine, although epinephrine has higher affinity.
This ligand-binding term supports the core beta-2 adrenergic receptor activity.
additional_reference_ids: &id036
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by: &id037
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: ADRB2 binds epinephrine (Epi) with an
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: approximately 30-fold greater affinity than norepinephrine (NE)
- reference_id: PMID:2831218
supporting_text: affinity for isoproterenol, epinephrine, and norepinephrine
- term:
id: GO:0004930
label: G protein-coupled receptor activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: Generic GPCR activity is correct but too broad for ADRB2.
action: MODIFY
reason: Replace the broad GPCR activity term with the more specific beta2-adrenergic receptor activity
already supported for ADRB2.
proposed_replacement_terms:
- id: GO:0004941
label: beta2-adrenergic receptor activity
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- term:
id: GO:0004935
label: adrenergic receptor activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: Generic adrenergic receptor activity is correct but less specific than beta2-adrenergic receptor
activity.
action: MODIFY
reason: ADRB2 is specifically the beta-2 adrenergic receptor, so the specific child term should be
used rather than a broader adrenergic receptor activity term.
proposed_replacement_terms:
- id: GO:0004941
label: beta2-adrenergic receptor activity
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: ADRB2 binds epinephrine (Epi) with an
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: approximately 30-fold greater affinity than norepinephrine (NE)
- reference_id: PMID:2831218
supporting_text: affinity for isoproterenol, epinephrine, and norepinephrine
- term:
id: GO:0004939
label: beta-adrenergic receptor activity
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: enables
review:
summary: Beta-adrenergic receptor activity is correct but less specific than beta2-adrenergic receptor
activity.
action: MODIFY
reason: ADRB2 should be annotated to beta2-adrenergic receptor activity rather than the broader beta-adrenergic
receptor parent.
proposed_replacement_terms:
- id: GO:0004941
label: beta2-adrenergic receptor activity
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: ADRB2 binds epinephrine (Epi) with an
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: approximately 30-fold greater affinity than norepinephrine (NE)
- reference_id: PMID:2831218
supporting_text: affinity for isoproterenol, epinephrine, and norepinephrine
- term:
id: GO:0004941
label: beta2-adrenergic receptor activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
action: ACCEPT
reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine
binding, Gs/Gi coupling, and adenylate cyclase signaling.
additional_reference_ids: *id001
supported_by: *id002
- term:
id: GO:0005794
label: Golgi apparatus
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: Golgi apparatus is a supported receptor itinerary location but not the primary active signaling
location.
action: KEEP_AS_NON_CORE
reason: Activated ADRB2 can traffic through the Golgi in a palmitoylation-dependent itinerary, but
the primary core location for receptor signaling is the plasma membrane.
additional_reference_ids: &id019
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:27481942
supported_by: &id020
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: Golgi apparatus
- reference_id: PMID:27481942
supporting_text: traffics along a previously undescribed intracellular itinerary via the Golgi complex
- reference_id: PMID:27481942
supporting_text: Cys-265 S-palmitoylation is mediated by the Golgi-resident palmitoyl transferases
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0006940
label: regulation of smooth muscle contraction
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: Regulation of smooth muscle contraction is broad vascular physiology context and is not directly
supported by the cached ADRB2 experiments.
action: MARK_AS_OVER_ANNOTATED
reason: The previous MARCH2 citation was introductory background rather than experimental support.
Because the cached evidence directly supports ADRB2 receptor signaling and trafficking rather than
smooth-muscle contraction regulation, this broad IEA physiology row should be treated as over-annotated.
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic
arterial blood pressure
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- term:
id: GO:0007186
label: G protein-coupled receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: Generic GPCR signaling is too broad for ADRB2.
action: MODIFY
reason: Replace the broad GPCR signaling pathway with adrenergic receptor signaling and, where appropriate,
the adenylate cyclase-activating adrenergic receptor signaling pathway.
proposed_replacement_terms:
- id: GO:0071875
label: adrenergic receptor signaling pathway
- id: GO:0071880
label: adenylate cyclase-activating adrenergic receptor signaling pathway
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- term:
id: GO:0007189
label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: Generic adenylate cyclase-activating GPCR signaling is too broad for ADRB2.
action: MODIFY
reason: Use the adrenergic receptor-specific adenylate cyclase-activating pathway term for ADRB2 rather
than the generic GPCR parent.
proposed_replacement_terms:
- id: GO:0071880
label: adenylate cyclase-activating adrenergic receptor signaling pathway
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: Membrane is correct but too broad for ADRB2 localization.
action: MODIFY
reason: ADRB2 is a multi-pass receptor whose core location is the plasma membrane; the generic membrane
term should be replaced with plasma membrane.
proposed_replacement_terms: &id025
- id: GO:0005886
label: plasma membrane
additional_reference_ids: &id026
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by: &id027
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cell membrane'
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: Multi-pass membrane protein
- reference_id: PMID:2831218
supporting_text: expression of the human beta 2-adrenergic receptor in mouse L cells
- term:
id: GO:0097746
label: blood vessel diameter maintenance
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: Blood vessel diameter maintenance is broad vascular physiology context and is not directly
supported by the cached ADRB2 experiments.
action: MARK_AS_OVER_ANNOTATED
reason: The previous MARCH2 citation was introductory background rather than experimental support.
The reviewed evidence supports catecholamine receptor signaling, but not a direct ADRB2-specific
blood-vessel-diameter maintenance assay, so this IEA row is over-annotated.
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic
arterial blood pressure
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17148612
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: &id005
- file:human/ADRB2/ADRB2-notes.md
supported_by: &id006
- reference_id: file:human/ADRB2/ADRB2-notes.md
supporting_text: Generic `protein binding` rows are not informative ADRB2 molecular functions
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17170700
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20353789
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23208550
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23236378
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23291003
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28298427
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32814053
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:36115835
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:39083597
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9671706
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:15518545
qualifier: enables
review:
summary: Identical protein binding reflects receptor oligomerization, but it is not ADRB2 core function.
action: KEEP_AS_NON_CORE
reason: ADRB2 oligomerization/hetero-oligomerization is supported, but the core molecular function
remains catecholamine receptor activity and downstream GPCR signaling.
additional_reference_ids: &id007
- PMID:15123695
- PMID:19763081
supported_by: &id008
- reference_id: PMID:15123695
supporting_text: hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic
signaling unit
- reference_id: PMID:19763081
supporting_text: Ligand-regulated oligomerization of beta(2)-adrenoceptors
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:19763081
qualifier: enables
review:
summary: Identical protein binding reflects receptor oligomerization, but it is not ADRB2 core function.
action: KEEP_AS_NON_CORE
reason: ADRB2 oligomerization/hetero-oligomerization is supported, but the core molecular function
remains catecholamine receptor activity and downstream GPCR signaling.
additional_reference_ids: *id007
supported_by: *id008
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:20590567
qualifier: enables
review:
summary: Identical protein binding reflects receptor oligomerization, but it is not ADRB2 core function.
action: KEEP_AS_NON_CORE
reason: ADRB2 oligomerization/hetero-oligomerization is supported, but the core molecular function
remains catecholamine receptor activity and downstream GPCR signaling.
additional_reference_ids: *id007
supported_by: *id008
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: located_in
review:
summary: Nucleus is not supported as a primary ADRB2 location.
action: MARK_AS_OVER_ANNOTATED
reason: The reviewed UniProt and publication evidence supports plasma membrane, endosomal/lysosomal
trafficking, and Golgi itinerary contexts, not a nuclear ADRB2 location.
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cell membrane'
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: Golgi apparatus
- term:
id: GO:0008179
label: adenylate cyclase binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: Adenylate cyclase binding is supported as receptor-effector complex context but is not the
core MF term.
action: KEEP_AS_NON_CORE
reason: ADRB2 can associate with adenylyl cyclase and channel-effector complexes, but beta2-adrenergic
receptor activity is the more direct core molecular function.
additional_reference_ids:
- PMID:12297500
supported_by:
- reference_id: PMID:12297500
supporting_text: beta(2)-adrenergic receptors (beta(2)-AR) form stable complexes with Kir3 channels
- reference_id: PMID:12297500
supporting_text: beta(2)AR interacts directly with Kir3.1/3.4 and Kir3.1/3.2c heterotetramers as
well as with adenylyl cyclase
- term:
id: GO:0010666
label: positive regulation of cardiac muscle cell apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Positive regulation of cardiac muscle cell apoptosis is a context-specific signaling output.
action: KEEP_AS_NON_CORE
reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context
outputs rather than the core receptor activity.
additional_reference_ids: &id011
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by: &id012
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction
rate
- term:
id: GO:0010667
label: negative regulation of cardiac muscle cell apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Negative regulation of cardiac muscle cell apoptosis is a context-specific signaling output.
action: KEEP_AS_NON_CORE
reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context
outputs rather than the core receptor activity.
additional_reference_ids: &id013
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by: &id014
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction
rate
- term:
id: GO:0016324
label: apical plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: located_in
review:
summary: Apical plasma membrane is plausible specialized plasma-membrane context, but not the primary
localization term.
action: KEEP_AS_NON_CORE
reason: ADRB2 is primarily a plasma-membrane GPCR; apical plasma membrane can be retained as cell-type
context but should not replace the core plasma membrane annotation.
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cell membrane'
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: Multi-pass membrane protein
- reference_id: PMID:2831218
supporting_text: expression of the human beta 2-adrenergic receptor in mouse L cells
- term:
id: GO:0019899
label: enzyme binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: Generic enzyme binding is not an informative ADRB2 molecular function.
action: MARK_AS_OVER_ANNOTATED
reason: ADRB2 has specific signaling and trafficking partners, but generic enzyme binding should not
be used as a functional endpoint when beta2-adrenergic receptor activity and specific pathway terms
are available.
additional_reference_ids:
- file:human/ADRB2/ADRB2-notes.md
supported_by:
- reference_id: file:human/ADRB2/ADRB2-notes.md
supporting_text: Specific interaction contexts such as receptor oligomerization
- term:
id: GO:0061885
label: positive regulation of mini excitatory postsynaptic potential
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Positive regulation of mini excitatory postsynaptic potential is a neuronal downstream context.
action: KEEP_AS_NON_CORE
reason: The amyloid-beta/AMPA receptor study supports a neuronal beta2AR signaling complex affecting
excitatory postsynaptic currents, but this is a specialized context rather than the core ADRB2 function.
additional_reference_ids:
- PMID:20395454
supported_by:
- reference_id: PMID:20395454
supporting_text: soluble Abeta binds to beta(2)AR
- reference_id: PMID:20395454
supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling
- reference_id: PMID:20395454
supporting_text: beta(2)AR and GluR1 also form a complex
- term:
id: GO:0071880
label: adenylate cyclase-activating adrenergic receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Adenylate cyclase-activating adrenergic receptor signaling is a core ADRB2 function.
action: ACCEPT
reason: The core beta-2 adrenergic receptor activity couples catecholamine binding to Gs, cAMP/PKA,
and adenylate cyclase signaling.
additional_reference_ids: *id009
supported_by: *id010
- term:
id: GO:0071881
label: adenylate cyclase-inhibiting adrenergic receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Adenylate cyclase-inhibiting adrenergic receptor signaling is supportable as the Gi arm of
ADRB2 signaling.
action: ACCEPT
reason: UniProt describes ADRB2 coupling to both Gs and Gi proteins; the Gi branch is part of bifurcated
beta-2 adrenergic receptor signaling even if it is more context-dependent than the canonical Gs/cAMP
arm.
additional_reference_ids: &id015
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:15123695
supported_by: &id016
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- term:
id: GO:0098992
label: neuronal dense core vesicle
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: is_active_in
review:
summary: Neuronal dense core vesicle is not supported as a primary ADRB2 active location.
action: MARK_AS_OVER_ANNOTATED
reason: The local evidence supports plasma membrane receptor activity and endosomal/Golgi trafficking.
Dense-core vesicle activity is not established by the reviewed ADRB2 publications.
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cell membrane'
- term:
id: GO:0106134
label: positive regulation of cardiac muscle cell contraction
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Positive regulation of cardiac muscle cell contraction is a downstream tissue-specific output.
action: KEEP_AS_NON_CORE
reason: Cardiomyocyte contraction-rate regulation is a physiological output of beta-adrenergic signaling
and is secondary to the core receptor activity.
additional_reference_ids: &id017
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by: &id018
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction
rate
- term:
id: GO:0120162
label: positive regulation of cold-induced thermogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Cold-induced thermogenesis is not supported as an ADRB2-specific annotation by the cited
triple-knockout study.
action: MARK_AS_OVER_ANNOTATED
reason: PMID:12387862 tests beta1/beta2/beta3 adrenoceptor triple-knockout mice, so its cold-intolerance
phenotype supports beta-adrenergic signaling broadly, not ADRB2 specifically. ADRB2-specific adipocyte
evidence supports cAMP-stimulated lipolysis, but not direct positive regulation of cold-induced
thermogenesis at the gene level.
additional_reference_ids: &id023
- PMID:23708524
supported_by: &id024
- reference_id: PMID:12387862
supporting_text: TKO mice exhibited normophagic obesity and cold-intolerance
- reference_id: PMID:12387862
supporting_text: beta-adrenergic signalling is essential for the resistance to obesity and cold
- reference_id: PMID:23708524
supporting_text: ADRB2-cAMP-stimulated lipolysis in fat cells
- term:
id: GO:1904646
label: cellular response to amyloid-beta
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Cellular response to amyloid-beta is a supported disease-context signaling response.
action: KEEP_AS_NON_CORE
reason: A beta binds beta2AR and induces PKA-dependent AMPA receptor hyperactivity, but this Alzheimer-disease-related
context is not ADRB2 core physiology.
additional_reference_ids: &id028
- PMID:20395454
supported_by: &id029
- reference_id: PMID:20395454
supporting_text: soluble Abeta binds to beta(2)AR
- reference_id: PMID:20395454
supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling
- reference_id: PMID:20395454
supporting_text: beta(2)AR and GluR1 also form a complex
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: EXP
original_reference_id: PMID:20559325
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: EXP
original_reference_id: PMID:25220262
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: EXP
original_reference_id: PMID:2831218
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: EXP
original_reference_id: PMID:7915137
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0071875
label: adrenergic receptor signaling pathway
evidence_type: IGI
original_reference_id: PMID:20395454
qualifier: involved_in
review:
summary: Adrenergic receptor signaling pathway is a core ADRB2 signaling annotation.
action: ACCEPT
reason: ADRB2 transduces catecholamine binding into adrenergic receptor signaling through G protein,
cAMP/PKA, beta-arrestin, and MAPK-associated branches.
additional_reference_ids: &id030
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
- PMID:10734107
supported_by: &id031
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- reference_id: PMID:10734107
supporting_text: beta(2)-Adrenergic receptor (beta(2)AR) stimulation of COS-7 cells induces EGFR
dimerization
- reference_id: PMID:10734107
supporting_text: beta(2)AR-dependent signaling to ERK1/2
- reference_id: PMID:15123695
supporting_text: regulate adenylyl cyclase and extracellular signal-regulated kinase activity
- term:
id: GO:1900451
label: positive regulation of glutamate receptor signaling pathway
evidence_type: IGI
original_reference_id: PMID:20395454
qualifier: involved_in
review:
summary: Positive regulation of glutamate receptor signaling is a neuronal amyloid-beta context.
action: KEEP_AS_NON_CORE
reason: The amyloid-beta study supports beta2AR/AMPA receptor complex signaling, but this is a specialized
neuronal disease-context output rather than the central ADRB2 function.
additional_reference_ids:
- PMID:20395454
supported_by:
- reference_id: PMID:20395454
supporting_text: soluble Abeta binds to beta(2)AR
- reference_id: PMID:20395454
supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling
- reference_id: PMID:20395454
supporting_text: beta(2)AR and GluR1 also form a complex
- term:
id: GO:0071880
label: adenylate cyclase-activating adrenergic receptor signaling pathway
evidence_type: IGI
original_reference_id: PMID:20395454
qualifier: involved_in
review:
summary: Adenylate cyclase-activating adrenergic receptor signaling is a core ADRB2 function.
action: ACCEPT
reason: The core beta-2 adrenergic receptor activity couples catecholamine binding to Gs, cAMP/PKA,
and adenylate cyclase signaling.
additional_reference_ids: *id009
supported_by: *id010
- term:
id: GO:0004941
label: beta2-adrenergic receptor activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: enables
review:
summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
action: ACCEPT
reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine
binding, Gs/Gi coupling, and adenylate cyclase signaling.
additional_reference_ids: *id001
supported_by: *id002
- term:
id: GO:0004941
label: beta2-adrenergic receptor activity
evidence_type: IMP
original_reference_id: PMID:2831218
qualifier: enables
review:
summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
action: ACCEPT
reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine
binding, Gs/Gi coupling, and adenylate cyclase signaling.
additional_reference_ids: *id001
supported_by: *id002
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:19584355
qualifier: is_active_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0010666
label: positive regulation of cardiac muscle cell apoptotic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: Positive regulation of cardiac muscle cell apoptosis is a context-specific signaling output.
action: KEEP_AS_NON_CORE
reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context
outputs rather than the core receptor activity.
additional_reference_ids: *id011
supported_by: *id012
- term:
id: GO:0010667
label: negative regulation of cardiac muscle cell apoptotic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: Negative regulation of cardiac muscle cell apoptosis is a context-specific signaling output.
action: KEEP_AS_NON_CORE
reason: Cardiomyocyte apoptotic/survival effects derive from bifurcated Gs/Gi signaling and are tissue-context
outputs rather than the core receptor activity.
additional_reference_ids: *id013
supported_by: *id014
- term:
id: GO:0071880
label: adenylate cyclase-activating adrenergic receptor signaling pathway
evidence_type: IC
original_reference_id: PMID:2831218
qualifier: involved_in
review:
summary: Adenylate cyclase-activating adrenergic receptor signaling is a core ADRB2 function.
action: ACCEPT
reason: The core beta-2 adrenergic receptor activity couples catecholamine binding to Gs, cAMP/PKA,
and adenylate cyclase signaling.
additional_reference_ids: *id009
supported_by: *id010
- term:
id: GO:0071881
label: adenylate cyclase-inhibiting adrenergic receptor signaling pathway
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: Adenylate cyclase-inhibiting adrenergic receptor signaling is supportable as the Gi arm of
ADRB2 signaling.
action: ACCEPT
reason: UniProt describes ADRB2 coupling to both Gs and Gi proteins; the Gi branch is part of bifurcated
beta-2 adrenergic receptor signaling even if it is more context-dependent than the canonical Gs/cAMP
arm.
additional_reference_ids: *id015
supported_by: *id016
- term:
id: GO:0106134
label: positive regulation of cardiac muscle cell contraction
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: Positive regulation of cardiac muscle cell contraction is a downstream tissue-specific output.
action: KEEP_AS_NON_CORE
reason: Cardiomyocyte contraction-rate regulation is a physiological output of beta-adrenergic signaling
and is secondary to the core receptor activity.
additional_reference_ids: *id017
supported_by: *id018
- term:
id: GO:0042803
label: protein homodimerization activity
evidence_type: IPI
original_reference_id: PMID:15123695
qualifier: enables
review:
summary: Protein homodimerization activity is supported receptor oligomerization context but not core
function.
action: KEEP_AS_NON_CORE
reason: ADRB2 can form receptor oligomers, but oligomerization is secondary to catecholamine receptor
activity and signaling.
additional_reference_ids:
- PMID:15123695
- PMID:19763081
supported_by:
- reference_id: PMID:15123695
supporting_text: hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic
signaling unit
- reference_id: PMID:19763081
supporting_text: Ligand-regulated oligomerization of beta(2)-adrenoceptors
- term:
id: GO:0044877
label: protein-containing complex binding
evidence_type: IPI
original_reference_id: PMID:20395454
qualifier: enables
review:
summary: Protein-containing complex binding is supported by the amyloid-beta/AMPA receptor complex
context.
action: KEEP_AS_NON_CORE
reason: The amyloid-beta study supports beta2AR participation in a postsynaptic signaling complex,
but this generic binding term is less informative than receptor activity and pathway-specific signaling
terms.
additional_reference_ids:
- PMID:20395454
supported_by:
- reference_id: PMID:20395454
supporting_text: soluble Abeta binds to beta(2)AR
- reference_id: PMID:20395454
supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling
- reference_id: PMID:20395454
supporting_text: beta(2)AR and GluR1 also form a complex
- term:
id: GO:0098990
label: AMPA selective glutamate receptor signaling pathway
evidence_type: IGI
original_reference_id: PMID:20395454
qualifier: involved_in
review:
summary: AMPA-selective glutamate receptor signaling is a specialized neuronal output.
action: KEEP_AS_NON_CORE
reason: Beta2AR can mediate amyloid-beta-induced AMPA receptor hyperactivity, but this is a disease/neuron
signaling branch rather than ADRB2 core function.
additional_reference_ids:
- PMID:20395454
supported_by:
- reference_id: PMID:20395454
supporting_text: soluble Abeta binds to beta(2)AR
- reference_id: PMID:20395454
supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling
- reference_id: PMID:20395454
supporting_text: beta(2)AR and GluR1 also form a complex
- term:
id: GO:0045744
label: negative regulation of G protein-coupled receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:15123695
qualifier: involved_in
review:
summary: Negative regulation of GPCR signaling is supported as receptor regulation/desensitization
context.
action: KEEP_AS_NON_CORE
reason: Hetero-oligomerization and beta-arrestin/endocytic regulation can dampen ADRB2 signaling,
but the central function remains receptor activation of adrenergic signaling pathways.
additional_reference_ids:
- PMID:15123695
- PMID:9507004
supported_by:
- reference_id: PMID:15123695
supporting_text: hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic
signaling unit
- reference_id: PMID:19763081
supporting_text: Ligand-regulated oligomerization of beta(2)-adrenoceptors
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: internalized into endosomes prior to their degradation in lysosomes
- term:
id: GO:0071880
label: adenylate cyclase-activating adrenergic receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:15123695
qualifier: involved_in
review:
summary: Adenylate cyclase-activating adrenergic receptor signaling is a core ADRB2 function.
action: ACCEPT
reason: The core beta-2 adrenergic receptor activity couples catecholamine binding to Gs, cAMP/PKA,
and adenylate cyclase signaling.
additional_reference_ids: *id009
supported_by: *id010
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23166351
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:23166351
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005794
label: Golgi apparatus
evidence_type: IDA
original_reference_id: PMID:27481942
qualifier: located_in
review:
summary: Golgi apparatus is a supported receptor itinerary location but not the primary active signaling
location.
action: KEEP_AS_NON_CORE
reason: Activated ADRB2 can traffic through the Golgi in a palmitoylation-dependent itinerary, but
the primary core location for receptor signaling is the plasma membrane.
additional_reference_ids: *id019
supported_by: *id020
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:27481942
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0030669
label: clathrin-coated endocytic vesicle membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868658
qualifier: located_in
review:
summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
action: KEEP_AS_NON_CORE
reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation
and sorting, but this is receptor lifecycle context rather than the core active signaling location.
additional_reference_ids: &id021
- PMID:9507004
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by: &id022
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: internalized into endosomes prior to their degradation in lysosomes
- reference_id: PMID:9507004
supporting_text: agonist-induced internalization and down-regulation of the beta2AR
- reference_id: PMID:9507004
supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes
- term:
id: GO:0030669
label: clathrin-coated endocytic vesicle membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868659
qualifier: located_in
review:
summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
action: KEEP_AS_NON_CORE
reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation
and sorting, but this is receptor lifecycle context rather than the core active signaling location.
additional_reference_ids: *id021
supported_by: *id022
- term:
id: GO:0030669
label: clathrin-coated endocytic vesicle membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868660
qualifier: located_in
review:
summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
action: KEEP_AS_NON_CORE
reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation
and sorting, but this is receptor lifecycle context rather than the core active signaling location.
additional_reference_ids: *id021
supported_by: *id022
- term:
id: GO:0030669
label: clathrin-coated endocytic vesicle membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868661
qualifier: located_in
review:
summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
action: KEEP_AS_NON_CORE
reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation
and sorting, but this is receptor lifecycle context rather than the core active signaling location.
additional_reference_ids: *id021
supported_by: *id022
- term:
id: GO:0030669
label: clathrin-coated endocytic vesicle membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8869438
qualifier: located_in
review:
summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
action: KEEP_AS_NON_CORE
reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation
and sorting, but this is receptor lifecycle context rather than the core active signaling location.
additional_reference_ids: *id021
supported_by: *id022
- term:
id: GO:0030669
label: clathrin-coated endocytic vesicle membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8871193
qualifier: located_in
review:
summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
action: KEEP_AS_NON_CORE
reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation
and sorting, but this is receptor lifecycle context rather than the core active signaling location.
additional_reference_ids: *id021
supported_by: *id022
- term:
id: GO:0030669
label: clathrin-coated endocytic vesicle membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8871194
qualifier: located_in
review:
summary: Clathrin-coated endocytic vesicle membrane is a supported receptor trafficking location.
action: KEEP_AS_NON_CORE
reason: Activated ADRB2 is internalized through clathrin-coated pits/vesicles during receptor down-regulation
and sorting, but this is receptor lifecycle context rather than the core active signaling location.
additional_reference_ids: *id021
supported_by: *id022
- term:
id: GO:0120162
label: positive regulation of cold-induced thermogenesis
evidence_type: ISS
original_reference_id: PMID:12387862
qualifier: involved_in
review:
summary: Cold-induced thermogenesis is not supported as an ADRB2-specific annotation by the cited
triple-knockout study.
action: MARK_AS_OVER_ANNOTATED
reason: PMID:12387862 tests beta1/beta2/beta3 adrenoceptor triple-knockout mice, so its cold-intolerance
phenotype supports beta-adrenergic signaling broadly, not ADRB2 specifically. ADRB2-specific adipocyte
evidence supports cAMP-stimulated lipolysis, but not direct positive regulation of cold-induced
thermogenesis at the gene level.
additional_reference_ids: *id023
supported_by: *id024
- term:
id: GO:0001540
label: amyloid-beta binding
evidence_type: IDA
original_reference_id: PMID:20395454
qualifier: enables
review:
summary: Amyloid-beta binding is direct but disease-context and not a core ADRB2 function.
action: KEEP_AS_NON_CORE
reason: Soluble amyloid beta binding to beta2AR is experimentally supported, but it is a specialized
Alzheimer-disease-related interaction rather than ADRB2 canonical catecholamine receptor function.
additional_reference_ids:
- PMID:20395454
supported_by:
- reference_id: PMID:20395454
supporting_text: soluble Abeta binds to beta(2)AR
- reference_id: PMID:20395454
supporting_text: binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling
- reference_id: PMID:20395454
supporting_text: beta(2)AR and GluR1 also form a complex
- term:
id: GO:0004941
label: beta2-adrenergic receptor activity
evidence_type: NAS
original_reference_id: PMID:20395454
qualifier: enables
review:
summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
action: ACCEPT
reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine
binding, Gs/Gi coupling, and adenylate cyclase signaling.
additional_reference_ids: *id001
supported_by: *id002
- term:
id: GO:0016020
label: membrane
evidence_type: NAS
original_reference_id: PMID:20395454
qualifier: located_in
review:
summary: Membrane is correct but too broad for ADRB2 localization.
action: MODIFY
reason: ADRB2 is a multi-pass receptor whose core location is the plasma membrane; the generic membrane
term should be replaced with plasma membrane.
proposed_replacement_terms: *id025
additional_reference_ids: *id026
supported_by: *id027
- term:
id: GO:1904646
label: cellular response to amyloid-beta
evidence_type: IGI
original_reference_id: PMID:20395454
qualifier: involved_in
review:
summary: Cellular response to amyloid-beta is a supported disease-context signaling response.
action: KEEP_AS_NON_CORE
reason: A beta binds beta2AR and induces PKA-dependent AMPA receptor hyperactivity, but this Alzheimer-disease-related
context is not ADRB2 core physiology.
additional_reference_ids: *id028
supported_by: *id029
- term:
id: GO:1990911
label: response to psychosocial stress
evidence_type: TAS
original_reference_id: PMID:20395454
qualifier: involved_in
review:
summary: Response to psychosocial stress is too high-level for a direct ADRB2 gene annotation from
the reviewed evidence.
action: MARK_AS_OVER_ANNOTATED
reason: The supporting ADRB2 evidence is receptor signaling and amyloid-beta neuronal signaling; a
broad organismal psychosocial-stress response annotation is not a precise gene-product function.
additional_reference_ids:
- PMID:20395454
supported_by:
- reference_id: PMID:20395454
supporting_text: non-neurotransmitter Abeta has a binding capacity to beta(2)AR
- term:
id: GO:0004941
label: beta2-adrenergic receptor activity
evidence_type: IDA
original_reference_id: PMID:19710023
qualifier: enables
review:
summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
action: ACCEPT
reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine
binding, Gs/Gi coupling, and adenylate cyclase signaling.
additional_reference_ids: *id001
supported_by: *id002
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:19710023
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0071875
label: adrenergic receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:19710023
qualifier: involved_in
review:
summary: Adrenergic receptor signaling pathway is a core ADRB2 signaling annotation.
action: ACCEPT
reason: ADRB2 transduces catecholamine binding into adrenergic receptor signaling through G protein,
cAMP/PKA, beta-arrestin, and MAPK-associated branches.
additional_reference_ids: *id030
supported_by: *id031
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5696968
qualifier: located_in
review:
summary: Endosome membrane is a supported post-endocytic receptor trafficking location.
action: KEEP_AS_NON_CORE
reason: Internalized ADRB2 is sorted between recycling and lysosomal routes from endosomes, but this
is secondary to the plasma-membrane receptor signaling role.
additional_reference_ids:
- PMID:9507004
- PMID:19424180
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: internalized into endosomes prior to their degradation in lysosomes
- reference_id: PMID:9507004
supporting_text: agonist-induced internalization and down-regulation of the beta2AR
- reference_id: PMID:9507004
supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes
- reference_id: PMID:19424180
supporting_text: sort internalized receptors to the lysosomes for degradation
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8851797
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8852167
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8866269
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8866283
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8867754
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8867756
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868071
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868072
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868230
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868236
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868648
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868651
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8868661
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8982641
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:1901098
label: positive regulation of autophagosome maturation
evidence_type: IDA
original_reference_id: PMID:23708524
qualifier: involved_in
review:
summary: Positive regulation of autophagosome maturation is supported in ADRB2-stimulated adipocyte
lipolysis but is non-core.
action: KEEP_AS_NON_CORE
reason: ADRB2 stimulation increases autophagy-targeted lipid droplets, but the direct lipophagy machinery
in the paper is RAB7; therefore this is retained as an upstream adipocyte signaling output rather
than a core ADRB2 function.
additional_reference_ids:
- PMID:23708524
- file:human/ADRB2/ADRB2-notes.md
supported_by:
- reference_id: PMID:23708524
supporting_text: ADRB2-stimulated lipolysis was reduced after inhibition of early or late autophagy
- reference_id: PMID:23708524
supporting_text: ADRB2 stimulation has caused a marked increase in the autophagy-targeted LDs for
lysosomal degradation
- reference_id: PMID:23708524
supporting_text: during ADRB2 stimulation, a subset of LDs are packaged into autophagosomes and
delivered to the lysosomes for degradation
- reference_id: PMID:23708524
supporting_text: RAB7 plays a pivotal role in the regulation of this autolysosome-mediated lipid
degradation in fat cells
- reference_id: file:human/ADRB2/ADRB2-notes.md
supporting_text: do not add direct `lipophagy` for ADRB2
- term:
id: GO:1904504
label: positive regulation of lipophagy
evidence_type: IDA
original_reference_id: PMID:23708524
qualifier: involved_in
review:
summary: Positive regulation of lipophagy is supported as upstream ADRB2 adipocyte signaling, but
should not be upgraded to direct lipophagy.
action: KEEP_AS_NON_CORE
reason: The PN projection to direct lipophagy is not accepted for ADRB2. PMID:23708524 supports ADRB2
stimulation as an upstream signal that increases lipophagy/autophagy-targeted lipid droplets, while
RAB7 is the direct lipid-droplet recruitment and autolysosomal degradation factor.
additional_reference_ids:
- PMID:23708524
- file:human/ADRB2/ADRB2-notes.md
supported_by:
- reference_id: PMID:23708524
supporting_text: ADRB2-stimulated lipolysis was reduced after inhibition of early or late autophagy
- reference_id: PMID:23708524
supporting_text: ADRB2 stimulation has caused a marked increase in the autophagy-targeted LDs for
lysosomal degradation
- reference_id: PMID:23708524
supporting_text: during ADRB2 stimulation, a subset of LDs are packaged into autophagosomes and
delivered to the lysosomes for degradation
- reference_id: PMID:23708524
supporting_text: RAB7 plays a pivotal role in the regulation of this autolysosome-mediated lipid
degradation in fat cells
- reference_id: file:human/ADRB2/ADRB2-notes.md
supporting_text: do not add direct `lipophagy` for ADRB2
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24405750
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0043235
label: signaling receptor complex
evidence_type: IDA
original_reference_id: PMID:23382219
qualifier: part_of
review:
summary: Signaling receptor complex is a supported core context for ADRB2 signaling.
action: ACCEPT
reason: ADRB2 functions in receptor-effector and receptor-scaffold complexes that support beta-adrenergic
signaling, including beta2/beta3 receptor signaling units and postsynaptic complexes.
additional_reference_ids: &id032
- PMID:15123695
- PMID:12297500
supported_by: &id033
- reference_id: PMID:15123695
supporting_text: hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic
signaling unit
- reference_id: PMID:19763081
supporting_text: Ligand-regulated oligomerization of beta(2)-adrenoceptors
- reference_id: PMID:12297500
supporting_text: beta(2)-adrenergic receptors (beta(2)-AR) form stable complexes with Kir3 channels
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20733053
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-379044
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-744886
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-744887
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8982645
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9609310
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9611751
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9611851
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19584355
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19424180
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:12297500
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0015459
label: potassium channel regulator activity
evidence_type: IDA
original_reference_id: PMID:12297500
qualifier: enables
review:
summary: Potassium channel regulator activity is supported receptor-effector context but not core
ADRB2 function.
action: KEEP_AS_NON_CORE
reason: ADRB2 can form stable complexes with Kir3 potassium channels and adenylyl cyclase, but this
specialized effector-complex role is secondary to beta2-adrenergic receptor activity.
additional_reference_ids:
- PMID:12297500
supported_by:
- reference_id: PMID:12297500
supporting_text: beta(2)-adrenergic receptors (beta(2)-AR) form stable complexes with Kir3 channels
- reference_id: PMID:12297500
supporting_text: beta(2)AR interacts directly with Kir3.1/3.4 and Kir3.1/3.2c heterotetramers as
well as with adenylyl cyclase
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:9235896
qualifier: located_in
review:
summary: Plasma membrane is the primary active location for ADRB2 catecholamine receptor signaling.
action: ACCEPT
reason: ADRB2 is a multi-pass cell-surface GPCR; plasma membrane localization is central to catecholamine
binding, G protein coupling, and downstream signaling.
additional_reference_ids: *id003
supported_by: *id004
- term:
id: GO:0004941
label: beta2-adrenergic receptor activity
evidence_type: IDA
original_reference_id: PMID:15123695
qualifier: enables
review:
summary: Beta2-adrenergic receptor activity is the core ADRB2 molecular function.
action: ACCEPT
reason: ADRB2 is the beta-2 adrenergic receptor; mutagenesis and UniProt evidence support catecholamine
binding, Gs/Gi coupling, and adenylate cyclase signaling.
additional_reference_ids: *id001
supported_by: *id002
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15123695
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0006898
label: receptor-mediated endocytosis
evidence_type: IDA
original_reference_id: PMID:15123695
qualifier: involved_in
review:
summary: Receptor-mediated endocytosis is supported receptor lifecycle regulation.
action: KEEP_AS_NON_CORE
reason: Agonist-induced beta2AR internalization and down-regulation are well supported, but this is
post-activation receptor trafficking rather than the primary receptor signaling function.
additional_reference_ids:
- PMID:9507004
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: internalized into endosomes prior to their degradation in lysosomes
- reference_id: PMID:9507004
supporting_text: agonist-induced internalization and down-regulation of the beta2AR
- reference_id: PMID:9507004
supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes
- term:
id: GO:0043235
label: signaling receptor complex
evidence_type: IDA
original_reference_id: PMID:15123695
qualifier: part_of
review:
summary: Signaling receptor complex is a supported core context for ADRB2 signaling.
action: ACCEPT
reason: ADRB2 functions in receptor-effector and receptor-scaffold complexes that support beta-adrenergic
signaling, including beta2/beta3 receptor signaling units and postsynaptic complexes.
additional_reference_ids: *id032
supported_by: *id033
- term:
id: GO:0043410
label: positive regulation of MAPK cascade
evidence_type: IDA
original_reference_id: PMID:15123695
qualifier: involved_in
review:
summary: Positive regulation of MAPK cascade is a supported ADRB2 signaling branch.
action: ACCEPT
reason: ADRB2 activates ERK/MAPK through beta-arrestin/Src/EGFR-associated receptor complexes, so
this is a real receptor signaling output rather than a project-level inference.
additional_reference_ids: *id034
supported_by: *id035
- term:
id: GO:0051380
label: norepinephrine binding
evidence_type: IDA
original_reference_id: PMID:15123695
qualifier: enables
review:
summary: Norepinephrine binding is supported as part of the catecholamine receptor activity.
action: ACCEPT
reason: ADRB2 binds catecholamines including norepinephrine, although epinephrine has higher affinity.
This ligand-binding term supports the core beta-2 adrenergic receptor activity.
additional_reference_ids: *id036
supported_by: *id037
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9560162
qualifier: enables
review:
summary: Generic protein binding is not an informative ADRB2 molecular-function annotation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction records identify many receptor partners, but GO protein binding does not describe
ADRB2 function. More informative terms are beta2-adrenergic receptor activity, catecholamine binding/signaling,
receptor-complex context, and specific trafficking or signaling outputs.
additional_reference_ids: *id005
supported_by: *id006
- term:
id: GO:0005764
label: lysosome
evidence_type: TAS
original_reference_id: PMID:9507004
qualifier: located_in
review:
summary: Lysosome is a supported destination for down-regulated ADRB2.
action: KEEP_AS_NON_CORE
reason: Activated/internalized ADRB2 can be routed to lysosomes for degradation, but lysosome localization
is receptor turnover context and not the core active signaling site.
additional_reference_ids:
- PMID:9507004
- PMID:19424180
- PMID:23166351
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: internalized into endosomes prior to their degradation in lysosomes
- reference_id: PMID:9507004
supporting_text: agonist-induced internalization and down-regulation of the beta2AR
- reference_id: PMID:9507004
supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes
- reference_id: PMID:19424180
supporting_text: sort internalized receptors to the lysosomes for degradation
- reference_id: PMID:20733053
supporting_text: recycling of the beta(2)-adrenoreceptor (beta(2)AR) from early endosomes
- reference_id: PMID:23166351
supporting_text: Lysosomal degradation of ubiquitinated beta(2)-adrenergic receptors
- term:
id: GO:0005768
label: endosome
evidence_type: TAS
original_reference_id: PMID:10734107
qualifier: located_in
review:
summary: Endosome is a supported post-endocytic ADRB2 trafficking compartment.
action: KEEP_AS_NON_CORE
reason: Internalized ADRB2 traffics through endosomes for recycling or lysosomal degradation, but
this is secondary to plasma-membrane signaling.
additional_reference_ids:
- PMID:9507004
- PMID:20733053
- file:human/ADRB2/ADRB2-uniprot.txt
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: internalized into endosomes prior to their degradation in lysosomes
- reference_id: PMID:9507004
supporting_text: agonist-induced internalization and down-regulation of the beta2AR
- reference_id: PMID:9507004
supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes
- reference_id: PMID:19424180
supporting_text: sort internalized receptors to the lysosomes for degradation
- reference_id: PMID:20733053
supporting_text: recycling of the beta(2)-adrenoreceptor (beta(2)AR) from early endosomes
- term:
id: GO:0007166
label: cell surface receptor signaling pathway
evidence_type: TAS
original_reference_id: PMID:1371121
qualifier: involved_in
review:
summary: Generic cell-surface receptor signaling is too broad for ADRB2.
action: MODIFY
reason: Replace this broad parent with adrenergic receptor signaling pathway and the adenylate cyclase-activating
adrenergic receptor signaling pathway where the evidence specifies cAMP/Gs signaling.
proposed_replacement_terms:
- id: GO:0071875
label: adrenergic receptor signaling pathway
- id: GO:0071880
label: adenylate cyclase-activating adrenergic receptor signaling pathway
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- term:
id: GO:0007188
label: adenylate cyclase-modulating G protein-coupled receptor signaling pathway
evidence_type: TAS
original_reference_id: PMID:2823249
qualifier: involved_in
review:
summary: Generic adenylate cyclase-modulating GPCR signaling is too broad for ADRB2.
action: MODIFY
reason: ADRB2 should be represented by adrenergic receptor signaling and its activating/inhibiting
adenylate cyclase adrenergic receptor branches rather than a generic GPCR signaling term.
proposed_replacement_terms:
- id: GO:0071880
label: adenylate cyclase-activating adrenergic receptor signaling pathway
- id: GO:0071881
label: adenylate cyclase-inhibiting adrenergic receptor signaling pathway
additional_reference_ids:
- file:human/ADRB2/ADRB2-uniprot.txt
- PMID:2831218
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- term:
id: GO:0008333
label: endosome to lysosome transport
evidence_type: TAS
original_reference_id: PMID:9507004
qualifier: involved_in
review:
summary: Endosome to lysosome transport is a supported ADRB2 down-regulation route.
action: KEEP_AS_NON_CORE
reason: ADRB2 can be sorted from endosomes to lysosomes for degradation during receptor down-regulation,
but this is a non-core receptor lifecycle process.
additional_reference_ids:
- PMID:9507004
- PMID:19424180
- PMID:23166351
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: internalized into endosomes prior to their degradation in lysosomes
- reference_id: PMID:9507004
supporting_text: agonist-induced internalization and down-regulation of the beta2AR
- reference_id: PMID:9507004
supporting_text: trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes
- reference_id: PMID:19424180
supporting_text: sort internalized receptors to the lysosomes for degradation
- reference_id: PMID:20733053
supporting_text: recycling of the beta(2)-adrenoreceptor (beta(2)AR) from early endosomes
- reference_id: PMID:23166351
supporting_text: Lysosomal degradation of ubiquitinated beta(2)-adrenergic receptors
core_functions:
- molecular_function:
id: GO:0004941
label: beta2-adrenergic receptor activity
description: ADRB2 binds catecholamines at the plasma membrane and activates beta-2 adrenergic receptor
signaling through Gs/cAMP/PKA, context-dependent Gi, and MAPK-associated signaling branches.
directly_involved_in:
- id: GO:0071880
label: adenylate cyclase-activating adrenergic receptor signaling pathway
- id: GO:0071881
label: adenylate cyclase-inhibiting adrenergic receptor signaling pathway
- id: GO:0043410
label: positive regulation of MAPK cascade
locations:
- id: GO:0005886
label: plasma membrane
supported_by:
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: G protein-coupled receptor for catecholamines that couples to
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: both G(s) and G(i) proteins, activating bifurcated signaling pathways
- reference_id: PMID:2831218
supporting_text: associated with high affinity ligand binding, Gs coupling, and adenylate cyclase
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: ADRB2 binds epinephrine (Epi) with an
- reference_id: file:human/ADRB2/ADRB2-uniprot.txt
supporting_text: approximately 30-fold greater affinity than norepinephrine (NE)
- reference_id: PMID:2831218
supporting_text: affinity for isoproterenol, epinephrine, and norepinephrine
- reference_id: PMID:10734107
supporting_text: beta(2)-Adrenergic receptor (beta(2)AR) stimulation of COS-7 cells induces EGFR dimerization
- reference_id: PMID:10734107
supporting_text: beta(2)AR-dependent signaling to ERK1/2
proposed_new_terms: []
suggested_questions:
- question: Should PN projection for ADRB2 remain at GO:1904504 positive regulation of lipophagy rather
than direct GO:0061724 lipophagy?
experts:
- GO autophagy editors
- Proteostasis Network curators
- question: Which ADRB2 trafficking locations should remain gene-level GO annotations versus pathway-context
annotations from receptor lifecycle studies?
experts:
- GO signaling editors
- GPCR trafficking experts
- question: Should endosomal/sustained beta2AR signaling (G protein activation from endosomes, beta-arrestin
megaplexes) be captured as a distinct active location or signaling context for ADRB2, or treated as
an emerging mechanism not yet at gene-annotation maturity?
experts:
- GO signaling editors
- GPCR trafficking experts
- question: Does ADRB2 biased agonism (e.g., beta-arrestin/NF-kB-selective outputs in immune cells) warrant
separate biological-process annotations distinct from canonical Gs/cAMP/PKA signaling?
experts:
- GPCR pharmacology experts
- GO signaling editors
suggested_experiments:
- description: Compare ADRB2 knockout/rescue and RAB7 knockout/rescue adipocytes during beta-adrenergic
stimulation using lipid-droplet autophagosome recruitment and lysosomal flux reporters.
hypothesis: ADRB2 acts upstream to stimulate lipophagy, whereas RAB7 is required for direct lipid-droplet
autolysosomal delivery.
- description: Measure endogenous ADRB2 routing to recycling versus lysosomal compartments after agonists
and biased ligands while perturbing ARRDC3, NEDD4, MARCH2, USP20/USP33, and SNX27.
hypothesis: Distinct trafficking adaptors determine whether activated ADRB2 is recycled/resensitized
or degraded after internalization.
- description: Use compartment-targeted cAMP/PKA biosensors with agonists and GRK/beta-arrestin perturbations
to test whether internalized ADRB2 sustains G protein signaling from endosomes versus only at the plasma
membrane.
hypothesis: A fraction of agonist-activated ADRB2 continues to generate cAMP from endosomes in a beta-arrestin-dependent
megaplex-like state, contributing a spatially distinct signaling output.
