ADRB3 encodes the beta-3 adrenergic receptor, a class A seven-transmembrane G protein-coupled receptor for the catecholamines noradrenaline and adrenaline (noradrenaline more potent), expressed mainly in white and brown adipocytes and also in detrusor and vascular smooth muscle, gallbladder and heart. Agonist-bound ADRB3 catalyses GDP/GTP exchange on heterotrimeric Gs and Gi: Gs activation of adenylyl cyclase and cAMP/PKA signaling drives adipocyte lipolysis and brown-fat thermogenesis, while constitutive Gi coupling restrains cAMP and triggers ERK1/2 activation. Unlike beta1 and beta2 receptors it has atypical pharmacology (low affinity for classical beta-blockers) and resists agonist-induced internalization, and it can hetero-oligomerize with the beta2 receptor. ADRB3 mediates relaxation of the urinary bladder (the target of beta3 agonists such as mirabegron for overactive bladder) and NO/cGMP-dependent negative inotropy in the human heart. Its contribution to human (as opposed to rodent) brown adipose tissue thermogenesis is debated, and the Trp64Arg variant has been associated with obesity and type 2 diabetes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002025 norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA (PTN002798518, mouse Adrb3 donor) placing ADRB3 in catecholamine-mediated vasodilation regulating systemic arterial pressure. Reason: ADRB3 is expressed in vasculature and mediates relaxation of blood vessels; a genuine but peripheral physiological output of the receptor, so retained as non-core. The PAINT node placement inside the ADRB3 clade is reasonable. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Participates in relaxation of the blood vessels and the urinary bladder Reactome:R-HSA-9611839 ADRB3 can also be found in the vasculature, the heart (Rozec & Gauthier 2006), gallbladder and urinary bladder |
| GO:0003925 G protein activity | IDA PMID:10207024 The beta3-adrenergic receptor activates mitogen-activated pr... | MODIFY | Summary: IDA from Soeder et al. 1999 (PMID:10207024), which shows beta3AR agonist stimulates GTP exchange on Galpha-s and Galpha-i in adipocyte membranes. Annotated as G protein activity. Reason: GO:0003925 G protein activity is_a GTPase activity and is defined as a molecular function regulator that cycles between GTP- and GDP-bound states and hydrolyses GTP with intrinsic GTPase activity; it describes the G protein alpha subunit (or a small GTPase), not the receptor. ADRB3 is a class A seven-transmembrane GPCR with no P-loop NTPase or Ras-like domain (InterPro IPR000276/IPR017452/IPR000681; Gene3D 1.20.1070.10 only), so it cannot bind and hydrolyse GTP itself. What PMID:10207024 measured is agonist (CL316,243)-stimulated incorporation of 8-azido-GTP into Galpha-s and Galpha-i: the receptor catalysing GDP/GTP exchange on its heterotrimeric G proteins, which is exactly the definition of G protein-coupled receptor activity (GO:0004930, 'promotes the exchange of GDP for GTP on the alpha subunit of a heterotrimeric G-protein complex'). The essence (ADRB3 activates Gs and Gi) is sound, so MODIFY to the most specific receptor term, GO:0015052 beta3-adrenergic receptor activity (is_a GO:0004930), which ADRB3 already carries by IDA from this same paper. Proposed replacements: beta3-adrenergic receptor activity Supporting Evidence: PMID:10207024 CL316,243 (5 microM) stimulated the incorporation of 8-azido-[32P]GTP into Galphas (1.57 +/- 0.12; n = 3) and Galphai (1. 68 +/- 0.13; n = 4) in adipocyte plasma membranes, directly demonstrating that beta3AR stimulation results in Gi-GTP exchange PMID:10207024 constitutive beta3AR coupling to Gi proteins serves both to restrain Gs-mediated activation of adenylyl cyclase and to initiate additional signal transduction pathways, including the ERK1/2 MAP kinase cascade |
| GO:0003925 G protein activity | IEA GO_REF:0000120 | MODIFY | Summary: Combined IEA (GO_REF:0000120) from ARBA00088750 and Ensembl Compara transfer from rat Adrb3, assigning G protein activity. Reason: GO:0003925 G protein activity is_a GTPase activity and is defined as a molecular function regulator that cycles between GTP- and GDP-bound states and hydrolyses GTP with intrinsic GTPase activity; it describes the G protein alpha subunit (or a small GTPase), not the receptor. ADRB3 is a class A seven-transmembrane GPCR with no P-loop NTPase or Ras-like domain (InterPro IPR000276/IPR017452/IPR000681; Gene3D 1.20.1070.10 only), so it cannot bind and hydrolyse GTP itself. What PMID:10207024 measured is agonist (CL316,243)-stimulated incorporation of 8-azido-GTP into Galpha-s and Galpha-i: the receptor catalysing GDP/GTP exchange on its heterotrimeric G proteins, which is exactly the definition of G protein-coupled receptor activity (GO:0004930, 'promotes the exchange of GDP for GTP on the alpha subunit of a heterotrimeric G-protein complex'). The essence (ADRB3 activates Gs and Gi) is sound, so MODIFY to the most specific receptor term, GO:0015052 beta3-adrenergic receptor activity (is_a GO:0004930), which ADRB3 already carries by IDA from this same paper. This electronic row inherits the same error from the rodent orthologs' UniProt IDA (same PMID:10207024) and from ARBA00088750, a P-loop G protein rule whose conditions ADRB3 does not appear to meet. Proposed replacements: beta3-adrenergic receptor activity Supporting Evidence: PMID:10207024 CL316,243 (5 microM) stimulated the incorporation of 8-azido-[32P]GTP into Galphas (1.57 +/- 0.12; n = 3) and Galphai (1. 68 +/- 0.13; n = 4) in adipocyte plasma membranes, directly demonstrating that beta3AR stimulation results in Gi-GTP exchange file:human/ADRB3/ADRB3-uniprot.txt Belongs to the G protein-coupled receptor 1 family |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO (IPR000276 rhodopsin-like GPCR) G protein-coupled receptor activity. Reason: Correct: ADRB3 is a class A GPCR that activates Gs and Gi. The term is less specific than the supported GO:0015052 beta3-adrenergic receptor activity (is_a GO:0004930), which the gene already carries by IBA and multiple IDA rows. Proposed replacements: beta3-adrenergic receptor activity Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively PMID:10207024 CL316,243 (5 microM) stimulated the incorporation of 8-azido-[32P]GTP into Galphas (1.57 +/- 0.12; n = 3) and Galphai (1. 68 +/- 0.13; n = 4) in adipocyte plasma membranes, directly demonstrating that beta3AR stimulation results in Gi-GTP exchange |
| GO:0004935 adrenergic receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO (IPR002233 adrenergic receptor family) adrenergic receptor activity. Reason: Correct but general; ADRB3 binds noradrenaline and adrenaline and signals as the beta3 subtype. Refine to GO:0015052 beta3-adrenergic receptor activity, already carried by the gene. Proposed replacements: beta3-adrenergic receptor activity Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively file:human/ADRB3/ADRB3-uniprot.txt The rank order of potency for physiological agonists is norepinephrine > epinephrine |
| GO:0004939 beta-adrenergic receptor activity | IDA PMID:15123695 Hetero-oligomerization between beta2- and beta3-adrenergic r... | MODIFY | Summary: IDA from Breit et al. 2004 (PMID:15123695): beta3AR regulates adenylyl cyclase and ERK via Gs and Gi/o in HEK293 cells. Reason: Correct but the parent of the supported subtype-specific term; refine to GO:0015052 beta3-adrenergic receptor activity, which the gene carries by IBA and IDA. Proposed replacements: beta3-adrenergic receptor activity Supporting Evidence: PMID:15123695 in contrast to beta(2)AR and beta(3)AR, which regulate adenylyl cyclase and extracellular signal-regulated kinase activity through a coupling to G(s) and G(i/o) |
| GO:0004939 beta-adrenergic receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO (IPR000681 beta-3 adrenoceptor) beta-adrenergic receptor activity. Reason: The InterPro entry is ADRB3-specific, so the subtype term GO:0015052 beta3-adrenergic receptor activity (child of this term, already carried) is the right level. Proposed replacements: beta3-adrenergic receptor activity Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively PMID:2570461 Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate |
| GO:0005515 protein binding | IPI PMID:15123695 Hetero-oligomerization between beta2- and beta3-adrenergic r... | MODIFY | Summary: IPI with ADRB2 (P07550) from BRET hetero-oligomerization assays (PMID:15123695). Reason: Generic protein binding is uninformative. The paper shows beta2AR and beta3AR form hetero-oligomers with the same propensity as beta2AR homo-oligomers, generating a signaling unit with altered trafficking and G protein selectivity; protein heterodimerization activity captures this better. Kept peripheral to the core receptor function. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:15123695 Quantitative bioluminescence resonance energy transfer titration curves revealed that the beta(2)AR has identical propensity to hetero-oligomerize with the beta(3)AR than to form homo-oligomers PMID:15123695 hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic signaling unit that possesses unique functional properties |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: IPI with RAMP2 (O60895) from a multiplexed suspension bead array screen of GPCR-RAMP interactions (PMID:39083597). Reason: Generic protein binding is uninformative under the protein-binding policy. The screen detects GPCR-RAMP complexes but the cached text gives no functional consequence of RAMP association for ADRB3 (no change in ligand specificity or trafficking), so no more informative molecular function can be assigned. Removal does not mean the interaction is false. Supporting Evidence: PMID:39083597 All potential GPCR-RAMP interacting pairs were expressed ectopically, solubilized and analyzed using the multiplexed suspension bead array (SBA) strategy. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: IPI with RAMP3 (O60896) from a multiplexed suspension bead array screen of GPCR-RAMP interactions (PMID:39083597). Reason: Generic protein binding is uninformative under the protein-binding policy. The screen detects GPCR-RAMP complexes but the cached text gives no functional consequence of RAMP association for ADRB3 (no change in ligand specificity or trafficking), so no more informative molecular function can be assigned. Removal does not mean the interaction is false. Supporting Evidence: PMID:39083597 All potential GPCR-RAMP interacting pairs were expressed ectopically, solubilized and analyzed using the multiplexed suspension bead array (SBA) strategy. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN002798190, adrenergic/aminergic receptor clade) plasma membrane. Reason: ADRB3 is a seven-transmembrane cell-surface receptor that binds circulating and neuronal catecholamines; plasma membrane localization is core and well placed phylogenetically. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein file:human/ADRB3/ADRB3-uniprot.txt Belongs to the G protein-coupled receptor 1 family |
| GO:0005886 plasma membrane | IDA PMID:19584355 Oxygen-regulated beta(2)-adrenergic receptor hydroxylation b... | ACCEPT | Summary: IDA plasma membrane from a study of beta2AR hydroxylation by EGLN3 (PMID:19584355). Reason: The cached full text is mainly about beta2AR and mentions beta3 only in passing; the beta3AR localization data are presumably in figures/supplement the curator saw. Plasma membrane localization of ADRB3 is not in doubt, so defer to the curator. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein PMID:10207024 CL316,243 (5 microM) stimulated the incorporation of 8-azido-[32P]GTP into Galphas (1.57 +/- 0.12; n = 3) and Galphai (1. 68 +/- 0.13; n = 4) in adipocyte plasma membranes, directly demonstrating that beta3AR stimulation results in Gi-GTP exchange |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (SL-0039 cell membrane). Reason: Consistent with the multi-pass GPCR topology of ADRB3. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0005886 plasma membrane | TAS PMID:1718744 Molecular characterization of the mouse beta 3-adrenergic re... | ACCEPT | Summary: TAS plasma membrane from the mouse beta3AR cloning paper (PMID:1718744). Reason: ADRB3 is a cell-surface GPCR; the location is correct and core. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein PMID:1718744 suggesting that the murine beta 3AR described here is the atypical beta AR involved in the control of energy expenditure in fat tissue |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379044 | ACCEPT | Summary: Reactome TAS plasma membrane (Reactome:R-HSA-379044), ADRB3 as the ligand-binding, Gs-activating receptor at the cell surface. Reason: Reactome places ligand binding and Gs activation by ADRB3 at the plasma membrane, consistent with its receptor topology. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein Reactome:R-HSA-379044 This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-744886 | ACCEPT | Summary: Reactome TAS plasma membrane (Reactome:R-HSA-744886), ADRB3 as the ligand-binding, Gs-activating receptor at the cell surface. Reason: Reactome places ligand binding and Gs activation by ADRB3 at the plasma membrane, consistent with its receptor topology. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein Reactome:R-HSA-379044 This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-744887 | ACCEPT | Summary: Reactome TAS plasma membrane (Reactome:R-HSA-744887), ADRB3 as the ligand-binding, Gs-activating receptor at the cell surface. Reason: Reactome places ligand binding and Gs activation by ADRB3 at the plasma membrane, consistent with its receptor topology. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein Reactome:R-HSA-379044 This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9609310 | ACCEPT | Summary: Reactome TAS plasma membrane (Reactome:R-HSA-9609310), ADRB3 as the ligand-binding, Gs-activating receptor at the cell surface. Reason: Reactome places ligand binding and Gs activation by ADRB3 at the plasma membrane, consistent with its receptor topology. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein Reactome:R-HSA-9611839 The Ξ²3-adrenergic receptor (ADRB3) is located mainly in adipose tissue and is involved in the regulation of lipolysis and thermogenesis |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9611839 | ACCEPT | Summary: Reactome TAS plasma membrane (Reactome:R-HSA-9611839), ADRB3 as the ligand-binding, Gs-activating receptor at the cell surface. Reason: Reactome places ligand binding and Gs activation by ADRB3 at the plasma membrane, consistent with its receptor topology. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein Reactome:R-HSA-9611839 The Ξ²3-adrenergic receptor (ADRB3) is located mainly in adipose tissue and is involved in the regulation of lipolysis and thermogenesis |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9611852 | ACCEPT | Summary: Reactome TAS plasma membrane (Reactome:R-HSA-9611852), ADRB3 as the ligand-binding, Gs-activating receptor at the cell surface. Reason: Reactome places ligand binding and Gs activation by ADRB3 at the plasma membrane, consistent with its receptor topology. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein Reactome:R-HSA-9611852 The catecholamines adrenaline (ADR) and noradrenaline (NaAd) are natural endogenous ligands that bind to Ξ²-adrenergic receptors |
| GO:0005975 carbohydrate metabolic process | TAS PMID:2570461 Molecular characterization of the human beta 3-adrenergic re... | MARK AS OVER ANNOTATED | Summary: TAS carbohydrate metabolic process from the human beta3AR cloning paper (PMID:2570461). Reason: The paper relates beta3AR agonist potency to 'various metabolic processes'; ADRB3 does not perform carbohydrate metabolism, it is a receptor whose signaling regulates adipocyte metabolism (lipolysis, thermogenesis). The process term overstates direct involvement. Supporting Evidence: PMID:2570461 The potency order of beta-AR agonists for the beta 3-AR correlates with their rank order for stimulating various metabolic processes in tissues where atypical adrenergic sites are thought to exist |
| GO:0006091 generation of precursor metabolites and energy | TAS PMID:2570461 Molecular characterization of the human beta 3-adrenergic re... | MARK AS OVER ANNOTATED | Summary: TAS generation of precursor metabolites and energy (PMID:2570461). Reason: ADRB3 regulates thermogenesis and lipolysis upstream via cAMP signaling; it does not itself generate precursor metabolites or energy. The better-supported regulatory terms (positive regulation of lipid catabolic process, positive regulation of cold-induced thermogenesis) are already present. Supporting Evidence: PMID:2570461 novel beta-AR agonists having high thermogenic, antiobesity, and antidiabetic activities in animal models are among the most potent stimulators of the beta 3-AR file:human/ADRB3/ADRB3-uniprot.txt Involved in the regulation of thermogenesis and lipolysis in brown and white adipose tissue |
| GO:0006112 energy reserve metabolic process | TAS PMID:1718744 Molecular characterization of the mouse beta 3-adrenergic re... | MODIFY | Summary: TAS energy reserve metabolic process from the mouse beta3AR cloning paper (PMID:1718744). Reason: ADRB3 controls energy expenditure in fat by signaling, i.e. it regulates triglyceride mobilization rather than performing energy-reserve metabolism. The regulatory term GO:0050996 positive regulation of lipid catabolic process (already carried) expresses this correctly. Proposed replacements: positive regulation of lipid catabolic process Supporting Evidence: PMID:1718744 suggesting that the murine beta 3AR described here is the atypical beta AR involved in the control of energy expenditure in fat tissue PMID:7493988 lacked functional beta 3-ARs, as demonstrated by complete loss of beta 3-agonist (CL 316,243)-induced stimulation of adenylate cyclase activity and lipolysis |
| GO:0006898 receptor-mediated endocytosis | IDA NOT PMID:15123695 Hetero-oligomerization between beta2- and beta3-adrenergic r... | ACCEPT | Summary: NOT receptor-mediated endocytosis, IDA (PMID:15123695): beta3AR resists agonist-promoted internalization. Reason: The negated annotation is supported: the paper states beta3AR is resistant to agonist-promoted endocytosis and that it acts as a dominant negative of beta2AR internalization in hetero-oligomers. Accept the NOT. Supporting Evidence: PMID:15123695 Given that the beta(3)AR is resistant to agonist-promoted endocytosis |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO G protein-coupled receptor signaling pathway. Reason: Correct but general; ADRB3 signaling is specifically adrenergic and both adenylate cyclase-activating (Gs) and -inhibiting (Gi). Refine to GO:0071880 and GO:0071881, both already carried. Proposed replacements: adenylate cyclase-activating adrenergic receptor signaling pathway adenylate cyclase-inhibiting adrenergic receptor signaling pathway Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively |
| GO:0007187 G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger | TAS PMID:2570461 Molecular characterization of the human beta 3-adrenergic re... | MODIFY | Summary: TAS GPCR signaling coupled to cyclic nucleotide second messenger (PMID:2570461; agonist-induced cAMP accumulation). Reason: Correct but general; the cAMP response is adenylate cyclase-activating adrenergic receptor signaling (GO:0071880), already carried. Proposed replacements: adenylate cyclase-activating adrenergic receptor signaling pathway Supporting Evidence: PMID:2570461 Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate |
| GO:0007188 adenylate cyclase-modulating G protein-coupled receptor signaling pathway | TAS PMID:1718744 Molecular characterization of the mouse beta 3-adrenergic re... | MODIFY | Summary: TAS adenylate cyclase-modulating GPCR signaling (PMID:1718744). Reason: Correct but general; refine to the adrenergic-specific activating (GO:0071880) and inhibiting (GO:0071881) pathway terms the gene already carries. Proposed replacements: adenylate cyclase-activating adrenergic receptor signaling pathway adenylate cyclase-inhibiting adrenergic receptor signaling pathway Supporting Evidence: PMID:1718744 suggesting that the murine beta 3AR described here is the atypical beta AR involved in the control of energy expenditure in fat tissue file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | MODIFY | Summary: Combined IEA adenylate cyclase-activating GPCR signaling pathway. Reason: Correct; the adrenergic-receptor-specific child GO:0071880 is supported by IDA and IBA and is the appropriate level. Proposed replacements: adenylate cyclase-activating adrenergic receptor signaling pathway Supporting Evidence: PMID:2570461 Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate PMID:7493988 lacked functional beta 3-ARs, as demonstrated by complete loss of beta 3-agonist (CL 316,243)-induced stimulation of adenylate cyclase activity and lipolysis |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IDA PMID:10207024 The beta3-adrenergic receptor activates mitogen-activated pr... | MODIFY | Summary: IDA (PMID:10207024): pertussis toxin enhances CL316,243-stimulated cAMP; beta3AR stimulates Gi-GTP exchange. Reason: ADRB3 couples to Gi in addition to Gs, restraining adenylyl cyclase and driving ERK1/2. The adrenergic-receptor-specific child GO:0071881 adenylate cyclase-inhibiting adrenergic receptor signaling pathway (already carried by IC) is the appropriate level. Proposed replacements: adenylate cyclase-inhibiting adrenergic receptor signaling pathway Supporting Evidence: PMID:10207024 CL316,243 (5 microM) stimulated the incorporation of 8-azido-[32P]GTP into Galphas (1.57 +/- 0.12; n = 3) and Galphai (1. 68 +/- 0.13; n = 4) in adipocyte plasma membranes, directly demonstrating that beta3AR stimulation results in Gi-GTP exchange PMID:10207024 constitutive beta3AR coupling to Gi proteins serves both to restrain Gs-mediated activation of adenylyl cyclase and to initiate additional signal transduction pathways, including the ERK1/2 MAP kinase cascade |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IDA PMID:9769330 The negative inotropic effect of beta3-adrenoceptor stimulat... | MODIFY | Summary: IDA (PMID:9769330): beta3AR negative inotropy in human ventricle via an NOS pathway. Reason: ADRB3 couples to Gi in addition to Gs, restraining adenylyl cyclase and driving ERK1/2. The adrenergic-receptor-specific child GO:0071881 adenylate cyclase-inhibiting adrenergic receptor signaling pathway (already carried by IC) is the appropriate level. The cached abstract of PMID:9769330 documents the NOS/cGMP mechanism rather than Gi directly (UniProt describes Gi/o involvement as 'possibly'); the full text was presumably seen by the curator, and the Gi branch itself is well supported by PMID:10207024 and PMID:15123695. Proposed replacements: adenylate cyclase-inhibiting adrenergic receptor signaling pathway Supporting Evidence: PMID:9769330 These results demonstrate that beta3-adrenoceptor stimulation decreases cardiac contractility through activation of an NOS pathway PMID:10207024 constitutive beta3AR coupling to Gi proteins serves both to restrain Gs-mediated activation of adenylyl cyclase and to initiate additional signal transduction pathways, including the ERK1/2 MAP kinase cascade PMID:15123695 in contrast to beta(2)AR and beta(3)AR, which regulate adenylyl cyclase and extracellular signal-regulated kinase activity through a coupling to G(s) and G(i/o) |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | MODIFY | Summary: Combined IEA adenylate cyclase-inhibiting GPCR signaling pathway (ARBA00043458 + rat ortholog). Reason: ADRB3 couples to Gi in addition to Gs, restraining adenylyl cyclase and driving ERK1/2. The adrenergic-receptor-specific child GO:0071881 adenylate cyclase-inhibiting adrenergic receptor signaling pathway (already carried by IC) is the appropriate level. Proposed replacements: adenylate cyclase-inhibiting adrenergic receptor signaling pathway Supporting Evidence: PMID:10207024 constitutive beta3AR coupling to Gi proteins serves both to restrain Gs-mediated activation of adenylyl cyclase and to initiate additional signal transduction pathways, including the ERK1/2 MAP kinase cascade |
| GO:0015052 beta3-adrenergic receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN002798518) beta3-adrenergic receptor activity; ADRB3 is among the experimental donors. Reason: Core molecular function: ADRB3 binds noradrenaline/adrenaline with beta3 pharmacology (low affinity for classical beta-blockers, potent activation by BRL37344/CL316,243) and activates Gs and Gi. The PAINT node is the ADRB3 clade and the target's own IDA supports it. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively PMID:2570461 Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate |
| GO:0015052 beta3-adrenergic receptor activity | IDA PMID:10188996 Functional and molecular biological evidence for a possible ... | ACCEPT | Summary: IDA (PMID:10188996): beta3 agonists relax human detrusor; SR58894A antagonist shifts isoprenaline response; ADRB3 mRNA present. Reason: Core molecular function: ADRB3 binds noradrenaline/adrenaline with beta3 pharmacology (low affinity for classical beta-blockers, potent activation by BRL37344/CL316,243) and activates Gs and Gi. Supporting Evidence: PMID:10188996 relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through beta3-AR activation |
| GO:0015052 beta3-adrenergic receptor activity | IDA PMID:10207024 The beta3-adrenergic receptor activates mitogen-activated pr... | ACCEPT | Summary: IDA (PMID:10207024): CL316,243 stimulates cAMP and Gs/Gi GTP exchange; human beta3AR reconstituted in HEK-293. Reason: Core molecular function: ADRB3 binds noradrenaline/adrenaline with beta3 pharmacology (low affinity for classical beta-blockers, potent activation by BRL37344/CL316,243) and activates Gs and Gi. Supporting Evidence: PMID:10207024 CL316,243 (5 microM) stimulated the incorporation of 8-azido-[32P]GTP into Galphas (1.57 +/- 0.12; n = 3) and Galphai (1. 68 +/- 0.13; n = 4) in adipocyte plasma membranes, directly demonstrating that beta3AR stimulation results in Gi-GTP exchange PMID:10207024 Expression of the human beta3AR in HEK-293 cells reconstituted the PTX-sensitive stimulation of MAP kinase |
| GO:0015052 beta3-adrenergic receptor activity | IDA PMID:2570461 Molecular characterization of the human beta 3-adrenergic re... | ACCEPT | Summary: IDA (PMID:2570461): cloning of human beta3AR; adrenaline/noradrenaline stimulate cAMP in transfected cells with atypical pharmacology. Reason: Core molecular function: ADRB3 binds noradrenaline/adrenaline with beta3 pharmacology (low affinity for classical beta-blockers, potent activation by BRL37344/CL316,243) and activates Gs and Gi. Supporting Evidence: PMID:2570461 Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate |
| GO:0015052 beta3-adrenergic receptor activity | IDA PMID:8641219 Pharmacological characterization of a recently described hum... | ACCEPT | Summary: IDA (PMID:8641219): human beta3AR (WT and W64R) expressed in CHO cells responds to agonists. Reason: Core molecular function: ADRB3 binds noradrenaline/adrenaline with beta3 pharmacology (low affinity for classical beta-blockers, potent activation by BRL37344/CL316,243) and activates Gs and Gi. Supporting Evidence: PMID:8641219 the W64R mutant receptor is pharmacologically and functionally indistinguishable from the wild type beta 3-adrenergic receptor |
| GO:0015052 beta3-adrenergic receptor activity | IDA PMID:9769330 The negative inotropic effect of beta3-adrenoceptor stimulat... | ACCEPT | Summary: IDA (PMID:9769330): beta3 agonist BRL37344 and noradrenaline (under alpha/beta1-2 blockade) reduce human ventricular contractility. Reason: Core molecular function: ADRB3 binds noradrenaline/adrenaline with beta3 pharmacology (low affinity for classical beta-blockers, potent activation by BRL37344/CL316,243) and activates Gs and Gi. Supporting Evidence: PMID:9769330 The negative inotropic effects of a beta3-adrenoceptor agonist, BRL 37344, and also of norepinephrine in the presence of alpha- and beta1-2-blockade |
| GO:0015052 beta3-adrenergic receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (ARBA00098039 + rat ortholog) beta3-adrenergic receptor activity. Reason: Core molecular function: ADRB3 binds noradrenaline/adrenaline with beta3 pharmacology (low affinity for classical beta-blockers, potent activation by BRL37344/CL316,243) and activates Gs and Gi. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively |
| GO:0015052 beta3-adrenergic receptor activity | IMP PMID:9892244 Polymorphism of the human beta3-adrenoceptor gene forms a we... | ACCEPT | Summary: IMP (PMID:9892244): beta3AR gene haplotype associated with altered receptor function. Reason: The cached record has no abstract; the curator presumably saw functional data on receptor variants in the full text. The function itself is well established for ADRB3, so defer to the curator. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively PMID:2570461 Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO membrane. Reason: Correct but general; ADRB3 is a multi-pass plasma membrane receptor, so refine to GO:0005886 plasma membrane, already carried. Proposed replacements: plasma membrane Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0042755 eating behavior | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara IEA eating behavior from rat Adrb3. Reason: The only evidence linking ADRB3 to feeding is that a pharmacological beta3 agonist reduces food intake in mice, an effect absent in knockouts; this is an indirect, drug-induced systemic effect, and ADRB3 is not a component of feeding-behaviour circuitry. Beta1/2/3 triple knockouts are normophagic. Supporting Evidence: PMID:7493988 increased energy expenditure (2-fold), and reduced food intake (by 45%). These effects were completely absent in beta 3-AR-deficient mice PMID:12387862 TKO mice exhibited normophagic obesity and cold-intolerance |
| GO:0042803 protein homodimerization activity | IDA PMID:15123695 Hetero-oligomerization between beta2- and beta3-adrenergic r... | KEEP AS NON CORE | Summary: IDA protein homodimerization activity (PMID:15123695; BRET). Reason: BRET in the paper assessed homo- and hetero-oligomerization of beta2AR/beta3AR; homo-oligomerization of beta3AR is plausible and probably shown in full-text titrations. Peripheral to the receptor's core signaling role. Supporting Evidence: PMID:15123695 Quantitative bioluminescence resonance energy transfer titration curves revealed that the beta(2)AR has identical propensity to hetero-oligomerize with the beta(3)AR than to form homo-oligomers |
| GO:0043235 signaling receptor complex | IDA PMID:15123695 Hetero-oligomerization between beta2- and beta3-adrenergic r... | KEEP AS NON CORE | Summary: IDA signaling receptor complex (PMID:15123695): beta2/beta3AR hetero-oligomer. Reason: The beta2/beta3 hetero-oligomer is a receptor complex with distinct trafficking and coupling properties; physiologic relevance in native tissues is not established, so non-core. Supporting Evidence: PMID:15123695 hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic signaling unit that possesses unique functional properties |
| GO:0043410 positive regulation of MAPK cascade | IDA PMID:15123695 Hetero-oligomerization between beta2- and beta3-adrenergic r... | MODIFY | Summary: IDA positive regulation of MAPK cascade (PMID:15123695): beta3AR regulates ERK activity through Gs and Gi/o. Reason: Correct, but the MAPK activated is ERK1/2; refine to GO:0070374 positive regulation of ERK1 and ERK2 cascade, already carried by IDA. Proposed replacements: positive regulation of ERK1 and ERK2 cascade Supporting Evidence: PMID:15123695 in contrast to beta(2)AR and beta(3)AR, which regulate adenylyl cyclase and extracellular signal-regulated kinase activity through a coupling to G(s) and G(i/o) PMID:10207024 constitutive beta3AR coupling to Gi proteins serves both to restrain Gs-mediated activation of adenylyl cyclase and to initiate additional signal transduction pathways, including the ERK1/2 MAP kinase cascade |
| GO:0045744 negative regulation of G protein-coupled receptor signaling pathway | IDA NOT PMID:15123695 Hetero-oligomerization between beta2- and beta3-adrenergic r... | ACCEPT | Summary: NOT negative regulation of GPCR signaling pathway, IDA (PMID:15123695). Reason: Accept the NOT: in beta2/beta3 hetero-oligomers ligand binding and isoproterenol potency for adenylyl cyclase were unchanged, so beta3AR does not dampen beta2AR signaling output; its effects are on trafficking (blocked internalization) and coupling selectivity. Assigned by HGNC-UCL from full text. Supporting Evidence: PMID:15123695 did not affect the potency of isoproterenol to stimulate adenylyl cyclase |
| GO:0045986 negative regulation of smooth muscle contraction | IDA PMID:10188996 Functional and molecular biological evidence for a possible ... | KEEP AS NON CORE | Summary: IDA negative regulation of smooth muscle contraction (PMID:10188996): beta3AR mediates detrusor relaxation. Reason: Well-supported tissue-level output of ADRB3 signaling (basis of beta3 agonist therapy for overactive bladder), but a physiological consequence rather than the receptor's molecular role. Supporting Evidence: PMID:10188996 relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through beta3-AR activation Reactome:R-HSA-9611839 Drugs such as solabegron (Schemann et al. 2010) and mirabegron (Gras 2012, Nitti et al. 2013) that act as Ξ²3-agonists are commonly used in the treatment of patients with overactive bladders |
| GO:0050996 positive regulation of lipid catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Adrb3 (P25962): positive regulation of lipid catabolic process (lipolysis). Reason: Lipolysis stimulation is a principal physiological role of ADRB3 in adipocytes: knockout mice lose agonist-stimulated lipolysis, and silencing ADRB3 in human brown/beige adipocytes reduces agonist-stimulated lipolysis. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Involved in the regulation of thermogenesis and lipolysis in brown and white adipose tissue PMID:7493988 lacked functional beta 3-ARs, as demonstrated by complete loss of beta 3-agonist (CL 316,243)-induced stimulation of adenylate cyclase activity and lipolysis PMID:34100382 we demonstrate that the Ξ²3-AR plays a critical role in regulating lipolysis, glycolysis, and thermogenesis |
| GO:0051379 epinephrine binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA epinephrine binding. Reason: ADRB3 is activated by adrenaline (lower potency than noradrenaline); ligand binding is integral to its receptor activity. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt The rank order of potency for physiological agonists is norepinephrine > epinephrine Reactome:R-HSA-9611852 The catecholamines adrenaline (ADR) and noradrenaline (NaAd) are natural endogenous ligands that bind to Ξ²-adrenergic receptors |
| GO:0051379 epinephrine binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara IEA epinephrine binding. Reason: As for the IBA row: adrenaline is an endogenous ADRB3 agonist. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt The rank order of potency for physiological agonists is norepinephrine > epinephrine PMID:2570461 Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate |
| GO:0051380 norepinephrine binding | IDA PMID:15123695 Hetero-oligomerization between beta2- and beta3-adrenergic r... | ACCEPT | Summary: IDA norepinephrine binding (PMID:15123695). Reason: Noradrenaline is the most potent physiological agonist of ADRB3; binding is integral to receptor activity. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt The rank order of potency for physiological agonists is norepinephrine > epinephrine PMID:2570461 Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate |
| GO:0051380 norepinephrine binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara IEA norepinephrine binding. Reason: Noradrenaline is the most potent physiological agonist of ADRB3. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt The rank order of potency for physiological agonists is norepinephrine > epinephrine |
| GO:0055118 negative regulation of cardiac muscle contraction | IDA PMID:9769330 The negative inotropic effect of beta3-adrenoceptor stimulat... | KEEP AS NON CORE | Summary: IDA negative regulation of cardiac muscle contraction (PMID:9769330). Reason: Beta3 stimulation decreases human ventricular contractility via eNOS/NO/cGMP; a genuine but tissue-specific output, non-core. Supporting Evidence: PMID:9769330 These results demonstrate that beta3-adrenoceptor stimulation decreases cardiac contractility through activation of an NOS pathway file:human/ADRB3/ADRB3-uniprot.txt Also mediates negative inotropic effects in cardiomyocytes through activation of an NO synthase pathway |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IDA PMID:10207024 The beta3-adrenergic receptor activates mitogen-activated pr... | ACCEPT | Summary: IDA positive regulation of ERK1 and ERK2 cascade (PMID:10207024). Reason: Beta3AR activates ERK1/2 through Gi in adipocytes and in HEK-293 cells expressing human ADRB3; a defining branch of its dual-coupling signaling. Supporting Evidence: PMID:10207024 constitutive beta3AR coupling to Gi proteins serves both to restrain Gs-mediated activation of adenylyl cyclase and to initiate additional signal transduction pathways, including the ERK1/2 MAP kinase cascade PMID:10207024 Expression of the human beta3AR in HEK-293 cells reconstituted the PTX-sensitive stimulation of MAP kinase |
| GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA adenylate cyclase-activating adrenergic receptor signaling pathway (PTN001205212; ADRB3 among donors). Reason: Core process: agonist-bound ADRB3 activates Gs and adenylyl cyclase, raising cAMP. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively PMID:2570461 Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate |
| GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway | IDA PMID:10188996 Functional and molecular biological evidence for a possible ... | ACCEPT | Summary: IDA (PMID:10188996). Reason: Core process: agonist-bound ADRB3 activates Gs and adenylyl cyclase, raising cAMP. Detrusor relaxation is mediated through beta3-AR activation. Supporting Evidence: PMID:10188996 relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through beta3-AR activation file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively |
| GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway | IDA PMID:15123695 Hetero-oligomerization between beta2- and beta3-adrenergic r... | ACCEPT | Summary: IDA (PMID:15123695). Reason: Core process: agonist-bound ADRB3 activates Gs and adenylyl cyclase, raising cAMP. Supporting Evidence: PMID:15123695 in contrast to beta(2)AR and beta(3)AR, which regulate adenylyl cyclase and extracellular signal-regulated kinase activity through a coupling to G(s) and G(i/o) |
| GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway | IDA PMID:8641219 Pharmacological characterization of a recently described hum... | ACCEPT | Summary: IDA (PMID:8641219). Reason: Core process: agonist-bound ADRB3 activates Gs and adenylyl cyclase, raising cAMP. Supporting Evidence: PMID:8641219 the W64R mutant receptor is pharmacologically and functionally indistinguishable from the wild type beta 3-adrenergic receptor file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively |
| GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (ARBA00097928 + rat ortholog). Reason: Core process: agonist-bound ADRB3 activates Gs and adenylyl cyclase, raising cAMP. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively |
| GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from O02662. Reason: Core process: agonist-bound ADRB3 activates Gs and adenylyl cyclase, raising cAMP. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively PMID:7493988 lacked functional beta 3-ARs, as demonstrated by complete loss of beta 3-agonist (CL 316,243)-induced stimulation of adenylate cyclase activity and lipolysis |
| GO:0071881 adenylate cyclase-inhibiting adrenergic receptor signaling pathway | IC PMID:9769330 The negative inotropic effect of beta3-adrenoceptor stimulat... | ACCEPT | Summary: IC adenylate cyclase-inhibiting adrenergic receptor signaling pathway (PMID:9769330, from GO:0015052). Reason: ADRB3 couples to Gi, restraining Gs-stimulated adenylyl cyclase; directly shown in PMID:10207024 and PMID:15123695. Supporting Evidence: PMID:10207024 constitutive beta3AR coupling to Gi proteins serves both to restrain Gs-mediated activation of adenylyl cyclase and to initiate additional signal transduction pathways, including the ERK1/2 MAP kinase cascade PMID:15123695 in contrast to beta(2)AR and beta(3)AR, which regulate adenylyl cyclase and extracellular signal-regulated kinase activity through a coupling to G(s) and G(i/o) file:human/ADRB3/ADRB3-uniprot.txt G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Adrb3 (GO_REF:0000024): positive regulation of cold-induced thermogenesis. Reason: ADRB3 is the principal adrenergic driver of rodent brown-fat thermogenesis (cAMP/PKA, lipolysis, UCP1). In human brown/beige adipocytes silencing ADRB3 impairs lipolysis and thermogenesis (PMID:34100382), although Blondin et al. argue human BAT thermogenesis is beta2-driven (PMID:32755608); the human weighting is raised as a suggested question. ISS from mouse is acceptable. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Involved in the regulation of thermogenesis and lipolysis in brown and white adipose tissue PMID:34100382 we demonstrate that the Ξ²3-AR plays a critical role in regulating lipolysis, glycolysis, and thermogenesis PMID:32755608 in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of Ξ²3-AR |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:12387862 Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese... | ACCEPT | Summary: ISS from mouse Adrb3 (PMID:12387862): positive regulation of cold-induced thermogenesis. Reason: ADRB3 is the principal adrenergic driver of rodent brown-fat thermogenesis (cAMP/PKA, lipolysis, UCP1). In human brown/beige adipocytes silencing ADRB3 impairs lipolysis and thermogenesis (PMID:34100382), although Blondin et al. argue human BAT thermogenesis is beta2-driven (PMID:32755608); the human weighting is raised as a suggested question. ISS from mouse is acceptable. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Involved in the regulation of thermogenesis and lipolysis in brown and white adipose tissue PMID:34100382 we demonstrate that the Ξ²3-AR plays a critical role in regulating lipolysis, glycolysis, and thermogenesis PMID:32755608 in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of Ξ²3-AR PMID:12387862 TKO mice exhibited normophagic obesity and cold-intolerance |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:7493988 Targeted disruption of the beta 3-adrenergic receptor gene. | ACCEPT | Summary: ISS from mouse Adrb3 (PMID:7493988): positive regulation of cold-induced thermogenesis. Reason: ADRB3 is the principal adrenergic driver of rodent brown-fat thermogenesis (cAMP/PKA, lipolysis, UCP1). In human brown/beige adipocytes silencing ADRB3 impairs lipolysis and thermogenesis (PMID:34100382), although Blondin et al. argue human BAT thermogenesis is beta2-driven (PMID:32755608); the human weighting is raised as a suggested question. ISS from mouse is acceptable. Supporting Evidence: file:human/ADRB3/ADRB3-uniprot.txt Involved in the regulation of thermogenesis and lipolysis in brown and white adipose tissue PMID:34100382 we demonstrate that the Ξ²3-AR plays a critical role in regulating lipolysis, glycolysis, and thermogenesis PMID:32755608 in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of Ξ²3-AR |
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Download this section (compressed HTML)Q: How much does ADRB3, versus ADRB2, contribute to human brown adipose tissue lipolysis and thermogenesis at physiological agonist concentrations?
Suggested experts: adipocyte biologists, GPCR pharmacologists
Q: Should GO provide guidance (or a taxon/domain check) to prevent receptor-stimulated G protein GTP exchange assays being annotated to GO:0003925 G protein activity rather than G protein-coupled receptor activity?
Suggested experts: GO editors, UniProt curators
Experiment: CRISPR knockout of ADRB3 versus ADRB2 in human brown adipocytes with rescue, measuring mirabegron- and noradrenaline-stimulated cAMP, lipolysis and UCP1-dependent respiration across agonist concentrations.
Hypothesis: ADRB3 makes a quantitatively significant, agonist-concentration-dependent contribution to human brown adipocyte thermogenesis distinct from ADRB2.
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