id: MODULE:beta_adrenergic_signaling title: Beta-adrenergic receptor signaling — epinephrine acting through ADRB1/ADRB2, Gs, adenylyl cyclase/cAMP, PKA-dependent Gi switching, and GRK/beta-arrestin desensitization description: >- The catecholamine hormone and neurotransmitter epinephrine (adrenaline) signals through the beta-1 and beta-2 adrenergic receptors (ADRB1, ADRB2), class A G protein-coupled receptors that couple to the stimulatory G protein. Agonist binding lets the receptor act as a guanine nucleotide exchange factor for G alpha s (GNAS); GTP-bound G alpha s stimulates adenylyl cyclase, and the cAMP produced activates protein kinase A (PKA), whose targets in cardiac myocytes include proteins of excitation-contraction coupling. The signal is limited at the G protein by the GTPase-accelerating activity of the RGS-domain sorting nexin SNX13 (RGS-PX1), a Gs-alpha-selective GTPase activator. The receptors are switched off by G protein-coupled receptor kinases (GRK2, GRK5), whose phosphorylation of the occupied receptor promotes binding of beta-arrestins (ARRB1, ARRB2); arrestin binding sterically blocks G protein coupling (desensitization) and targets the receptor to clathrin-mediated internalization. PKA also phosphorylates the receptors; for ADRB2 this both uncouples it from Gs (heterologous desensitization) and switches its coupling to inhibitory Gi proteins. status: DRAFT scope: CONCRETE references: - id: PMID:2163110 title: "beta-Arrestin: a protein that regulates beta-adrenergic receptor function." reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Lohse et al., Science 1990); the discovery of beta-arrestin as the cofactor of beta-adrenergic receptor kinase (GRK2) in homologous desensitization. Abstract only. - id: PMID:9363896 title: Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Daaka et al., Nature 1997); PKA phosphorylation of ADRB2 switches its coupling from Gs to Gi in HEK293 cells. Abstract only. - id: PMID:11729322 title: RGS-PX1, a GAP for GalphaS and sorting nexin in vesicular trafficking. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Zheng et al., Science 2001); identifies SNX13 (RGS-PX1) as a Gs-alpha-specific GTPase-activating protein. GOA cites it for SNX13 positive regulation of GTPase activity (IDA). Abstract only. evidence: - source_id: PW:0000794 title: epinephrine signaling pathway via adrenergic receptor beta statement: >- The module boundary and its gene products follow the RGD diagram for this Pathway Ontology term: epinephrine associated with Adrb1 and Adrb2; both receptors associated with Gnas and with Arrb1 and Arrb2; Adrbk1 (GRK2) and Grk5 acting negatively on both receptors; Snx13 acting negatively on Gnas; the Galphas pathway leading to cAMP and the PKA signaling pathway; and receptor-G protein uncoupling, receptor internalization and beta-arrestin mediated signaling as labelled outcomes. The record text describes the Gs GEF cycle, RGS GAP termination, PKA and GRK phosphorylation of the receptors and arrestin-mediated desensitization. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000794.yaml). - source_id: GO:0071880 title: adenylate cyclase-activating adrenergic receptor signaling pathway statement: >- The module is grounded in this GO process, the curated skos:closeMatch for PW:0000794 in the project's PW-GO mappings. The ADRB2 Gi-switching branch is its sibling, adenylate cyclase-inhibiting adrenergic receptor signaling pathway (GO:0071881). notes: >- Derived from the RGD Pathway Ontology diagram PW:0000794 through the RGD_PATHWAY_ONTOLOGY project, as one of four mutually consistent Gs-coupled hormone receptor modules (crh_receptor_signaling, beta_adrenergic_signaling, pth_receptor_signaling, glucagon_receptor_signaling) that share one structure: ligand -> receptor -> Gs -> adenylyl cyclase/cAMP -> PKA (the last two included by reference to modules/gpcr_camp_pka_signaling.yaml) -> termination by GRK phosphorylation and beta-arrestin binding. Molecular functions were taken from each protein's experimental GO annotations in QuickGO and from the completed gene reviews where they exist (ADRB2 core GO:0004941 with GO:0071880 and GO:0071881; GRK2 and GRK5 core GO:0004703), and verified against go-basic (releases/2026-07-26): ADRB1 GO:0004940 IDA, GNAS P63092 GO:0003925 IDA, ARRB1/ARRB2 GO:0030674 IDA. Ligand. Epinephrine is a small molecule with no gene product, so it is recorded as the module's condition ((R)-adrenaline, CHEBI:28918, the natural enantiomer) rather than as an annoton. Its biosynthesis (RGD subpathway PW:0000803 epinephrine biosynthetic pathway) is ligand supply and is the separate module modules/catecholamine_biosynthesis.yaml. Both receptors also respond to norepinephrine; the RGD diagram and this module are scoped to epinephrine, which the record text calls the favoured beta-receptor agonist. ADRB3 is not on the RGD diagram and is not modelled. SNX13. RGD draws Snx13 as acting negatively on Gnas. SNX13 is RGS-PX1, a sorting nexin with an RGS domain; its RGS domain binds G alpha s, accelerates its GTP hydrolysis and attenuates Gs signalling (PMID:11729322), so it is the RGS-family GAP that the record text describes terminating the G protein signal, and it is modelled as a negative regulator of the Gs step with GO:0005096 GTPase activator activity. GOA has no SNX13 GTPase activator MF row; the IDA row from the same paper is the process positive regulation of GTPase activity (GO:0043547), so the MF is an author-supplied refinement documented by the quoted abstract. Its PX-domain sorting-nexin role in endosomal trafficking is outside the module. ADRB2 Gi switching. PKA phosphorylation of ADRB2 switches its coupling from Gs to Gi (PMID:9363896; the ADRB2 review accepts GO:0071881, and gomodel:680ad14200005738 models ADRB2-Gi-ADCY6). It is modelled as an optional regulatory part fed by PKA, with the ADRB2 annoton carrying the inhibitory process; the Gi alpha subunits are not on the RGD gene list and are left to the Gi arm of modules/gpcr_camp_pka_signaling.yaml in prose. The same PKA phosphorylation that drives switching also uncouples ADRB2 from Gs (heterologous desensitization), recorded on the PKA-to-switch connection. Whether ADRB1 switches similarly is not asserted. Termination. GRK2 (RGD Adrbk1) and GRK5 phosphorylate the occupied receptors and beta-arrestins bind them (PMID:2163110). The G protein-independent beta-arrestin scaffolding of MAPK cascades, which RGD labels "beta-arrestin mediated signaling", is a downstream output outside the module, as are the cardiac and smooth-muscle outputs of PKA. Arrestin-driven clathrin-mediated endocytosis is represented by the internalization process on the arrestin annoton only. Shared steps by reference. Adenylyl cyclase and PKA/CREB are module_refs to the generic modules/gpcr_camp_pka_signaling.yaml; RGD names no cyclase isoform (the beta-adrenergic GO-CAMs use ADCY6). That module already uses ADRB2 as its receptor exemplar; this module is the concrete beta-adrenergic instantiation. GO-CAM grounding. Receptor and GNAS annotons are linked to the human adrenaline-ADRB1 (gomodel:680ad14200003171) and adrenaline-ADRB2 (gomodel:680ad14200005774) Gs models, the Gi switch to gomodel:680ad14200005738, and the GRK and arrestin annotons to the GRK2/GRK3/arrestin desensitization model gomodel:67f85f2b00004426 (built for C5AR1, so gene and function match but not the receptor). Gene reviews exist for ADRB2, GRK2 and GRK5; the GNAS review in the repository is for the NESP55 accession O95467, not Gs alpha. module: id: beta_adrenergic_signaling label: Beta-adrenergic receptor signaling module_type: SIGNALING_PATHWAY concepts: - preferred_term: adenylate cyclase-activating adrenergic receptor signaling pathway term: id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway description: >- Epinephrine binding to ADRB1/ADRB2 and the resulting Gs-adenylyl cyclase-cAMP-PKA response, limited by SNX13 and terminated by GRK/beta-arrestin desensitization. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens description: >- Members are grounded on the human proteins; the pathway is conserved across mammals and the diagram is RGD's rat curation. cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane description: Receptors, Gs and the GRK/arrestin step act at the plasma membrane. conditions: - preferred_term: epinephrine (adrenaline) term: id: CHEBI:28918 label: (R)-adrenaline description: >- The small-molecule agonist of the module; not a gene product, so it has no annoton. parts: - order: 1 role: beta-adrenergic receptor activation by epinephrine node: id: beta_receptors label: ADRB1 and ADRB2 receptors module_type: REGULATORY_STEP description: >- Epinephrine-occupied beta-1 or beta-2 adrenergic receptors act as guanine nucleotide exchange factors for Gs. variant_sets: - id: beta_receptor_paralogs label: Beta-adrenergic receptors axis: receptor paralog selection: ONE_OR_MORE notes: >- ADRB1 is highest in heart and brain; ADRB2 is in heart, lung and smooth muscle. Both couple to Gs (PW:0000794 record text). variants: - id: adrb1_variant label: Beta-1 adrenergic receptor (ADRB1) module_type: REGULATORY_STEP annotons: - id: adrb1_receptor label: ADRB1 beta1-adrenergic receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ADRB1 term: id: UniProtKB:P08588 label: Beta-1 adrenergic receptor function: preferred_term: beta1-adrenergic receptor activity term: id: GO:0004940 label: beta1-adrenergic receptor activity processes: - preferred_term: adenylate cyclase-activating adrenergic receptor signaling pathway term: id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Cardiac and brain beta receptor; activates Gs on epinephrine binding. gocam_associations: - model: gomodel:680ad14200003171 activity: gomodel:680ad14200003171/680ad14200003172 title: Signaling by adrenaline mediated by ADRB1 receptor via G-alpha-s (activatory) (Human) description: Same gene and molecular function (GO:0004940). - id: adrb2_variant label: Beta-2 adrenergic receptor (ADRB2) module_type: REGULATORY_STEP annotons: - id: adrb2_receptor label: ADRB2 beta2-adrenergic receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ADRB2 term: id: UniProtKB:P07550 label: Beta-2 adrenergic receptor function: preferred_term: beta2-adrenergic receptor activity term: id: GO:0004941 label: beta2-adrenergic receptor activity processes: - preferred_term: adenylate cyclase-activating adrenergic receptor signaling pathway term: id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Beta-2 receptor; activates Gs on epinephrine binding. evidence: - source_id: PMID:9363896 statement: Most ADRB2 actions are mediated through Gs and PKA. supporting_text: >- most of the actions of the prototype beta2-adrenergic receptor are mediated through Gs proteins and the cyclic-AMP-dependent protein kinase (PKA) system gocam_associations: - model: gomodel:680ad14200005774 activity: gomodel:680ad14200005774/680ad14200005775 title: Signaling by adrenaline mediated by ADRB2 receptor via G-alpha-s (activatory)_Cardiomyocyte contraction (Human) description: Same gene, molecular function (GO:0004941) and process (GO:0071880). - order: 2 role: Gs activation node: id: beta_gs label: Gs alpha (GNAS) activation module_type: REGULATORY_STEP description: >- GTP-bound G alpha s dissociates from the receptor and G beta-gamma and stimulates adenylyl cyclase; its slow intrinsic GTPase returns it to the inactive heterotrimer. annotons: - id: beta_gnas label: GNAS G protein activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAS (G alpha s) term: id: UniProtKB:P63092 label: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: adenylate cyclase-activating adrenergic receptor signaling pathway term: id: GO:0071880 label: adenylate cyclase-activating adrenergic receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Stimulatory G alpha subunit coupling ADRB1/ADRB2 to adenylyl cyclase. gocam_associations: - model: gomodel:680ad14200003171 activity: gomodel:680ad14200003171/680ad14200003174 title: Signaling by adrenaline mediated by ADRB1 receptor via G-alpha-s (activatory) (Human) description: Same gene and molecular function (GO:0003925), ADRB1 arm. - model: gomodel:680ad14200005774 activity: gomodel:680ad14200005774/680ad14200005777 title: Signaling by adrenaline mediated by ADRB2 receptor via G-alpha-s (activatory)_Cardiomyocyte contraction (Human) description: Same gene and molecular function (GO:0003925), ADRB2 arm. - order: 3 role: Gs GTPase acceleration by SNX13 (regulation) optional: true node: id: beta_snx13_gap label: SNX13 (RGS-PX1) accelerates G alpha s GTP hydrolysis module_type: REGULATORY_STEP description: >- The RGS domain of the sorting nexin SNX13 is a G alpha s-selective GTPase activator that shortens the lifetime of active G alpha s-GTP. annotons: - id: snx13_gap label: SNX13 GTPase activator activity toward G alpha s participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SNX13 (RGS-PX1) term: id: UniProtKB:Q9Y5W8 label: Sorting nexin-13 function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity targets: - preferred_term: GNAS (G alpha s) term: id: UniProtKB:P63092 label: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short processes: - preferred_term: negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway term: id: GO:0106072 label: negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway role_description: RGS-domain GAP that terminates the Gs signal. evidence: - source_id: PMID:11729322 statement: >- The SNX13 (RGS-PX1) RGS domain binds G alpha s, accelerates its GTP hydrolysis and attenuates Gs signalling. supporting_text: >- The RGS domain of RGS-PX1 specifically interacted with Galpha(s), accelerated its GTP hydrolysis, and attenuated Galpha(s)-mediated signaling. - order: 4 role: adenylyl cyclase produces cAMP node: id: beta_adenylyl_cyclase label: Adenylyl cyclase produces cAMP description: >- Included by reference to the adenylyl cyclase step of the generic Gs-cAMP-PKA module; no cyclase isoform is asserted. module_ref: gpcr_camp_pka_signaling#adenylyl_cyclase_activation - order: 5 role: PKA activation and output node: id: beta_pka label: PKA activation and substrate phosphorylation description: >- Included by reference to the PKA/CREB step of the generic Gs-cAMP-PKA module; the cardiac excitation-contraction targets of PKA are outputs outside this module. module_ref: gpcr_camp_pka_signaling#pka_creb_output - order: 6 role: PKA-dependent switching of ADRB2 from Gs to Gi (documented variant) optional: true node: id: beta_adrb2_gi_switch label: PKA-phosphorylated ADRB2 couples to Gi module_type: REGULATORY_STEP description: >- PKA phosphorylation of ADRB2 uncouples it from Gs and switches it to inhibitory Gi proteins, whose beta-gamma subunits drive a Src/Ras/MAP kinase route and whose G alpha i inhibits adenylyl cyclase. annotons: - id: adrb2_gi_receptor label: ADRB2 receptor activity coupled to Gi participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ADRB2 term: id: UniProtKB:P07550 label: Beta-2 adrenergic receptor function: preferred_term: beta2-adrenergic receptor activity term: id: GO:0004941 label: beta2-adrenergic receptor activity processes: - preferred_term: adenylate cyclase-inhibiting adrenergic receptor signaling pathway term: id: GO:0071881 label: adenylate cyclase-inhibiting adrenergic receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: PKA-phosphorylated ADRB2 in its Gi-coupled state. evidence: - source_id: PMID:9363896 statement: PKA phosphorylation of ADRB2 switches its coupling from Gs to Gi. supporting_text: >- also serves to 'switch' coupling of this receptor from Gs to Gi and initiate a new set of signalling events. gocam_associations: - model: gomodel:680ad14200005738 activity: gomodel:680ad14200005738/680ad14200005739 title: Signaling by adrenaline mediated by ADRB2 receptor via G-alpha-i (inhibitory)_Cardioprotection (Human) description: Same gene, molecular function (GO:0004941) and process (GO:0071881). - order: 7 role: receptor desensitization (termination) node: id: beta_termination label: GRK phosphorylation and beta-arrestin desensitization of beta receptors module_type: REGULATORY_STEP description: >- GRK2 and GRK5 phosphorylate the agonist-occupied receptors; beta-arrestins bind the phosphorylated receptors, sterically prevent Gs coupling and target them to clathrin-coated pits for internalization. annotons: - id: beta_grk label: GRK2/GRK5 phosphorylation of beta-adrenergic receptors participant: selector_type: FAMILY family: preferred_term: G protein-coupled receptor kinases GRK2 and GRK5 representative_members: - preferred_term: GRK2 (beta-adrenergic receptor kinase 1) term: id: UniProtKB:P25098 label: G protein-coupled receptor kinase 2 - preferred_term: GRK5 term: id: UniProtKB:P34947 label: G protein-coupled receptor kinase 5 function: preferred_term: G protein-coupled receptor kinase activity term: id: GO:0004703 label: G protein-coupled receptor kinase activity targets: - preferred_term: ADRB1 term: id: UniProtKB:P08588 label: Beta-1 adrenergic receptor - preferred_term: ADRB2 term: id: UniProtKB:P07550 label: Beta-2 adrenergic receptor processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Phosphorylate the occupied receptors, the first step of homologous desensitization. gocam_associations: - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004469 title: Desensitization of C5AR1-mediated signaling following phosphorylation by GRK2 or GRK3 (Human). description: >- GRK2 with the same molecular function (GO:0004703) and process (GO:0002029), modelled on C5AR1 rather than a beta-adrenergic receptor. - id: beta_arrestin label: Beta-arrestin uncoupling and internalization of beta-adrenergic receptors participant: selector_type: FAMILY family: preferred_term: beta-arrestins (ARRB1, ARRB2) representative_members: - preferred_term: ARRB1 (beta-arrestin-1) term: id: UniProtKB:P49407 label: Beta-arrestin-1 - preferred_term: ARRB2 (beta-arrestin-2) term: id: UniProtKB:P32121 label: Beta-arrestin-2 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity targets: - preferred_term: ADRB2 term: id: UniProtKB:P07550 label: Beta-2 adrenergic receptor processes: - preferred_term: G protein-coupled receptor internalization term: id: GO:0002031 label: G protein-coupled receptor internalization locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Bind GRK-phosphorylated receptors, block Gs coupling and drive clathrin-mediated internalization; also scaffold G protein-independent MAPK signalling (outside the module). evidence: - source_id: PMID:2163110 statement: >- Beta-arrestin inhibits signalling by beta-adrenergic receptors that have been phosphorylated by beta-adrenergic receptor kinase (GRK2). supporting_text: >- It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. gocam_associations: - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004504 title: Desensitization of C5AR1-mediated signaling following phosphorylation by GRK2 or GRK3 (Human). description: ARRB1 with the same molecular function (GO:0030674), modelled on C5AR1. - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004511 title: Desensitization of C5AR1-mediated signaling following phosphorylation by GRK2 or GRK3 (Human). description: ARRB2 with the same molecular function (GO:0030674), modelled on C5AR1. connections: - source: beta_receptors target: beta_gs connection_type: POSITIVELY_REGULATES description: Epinephrine-occupied ADRB1/ADRB2 activate Gs. - source: beta_snx13_gap target: beta_gs connection_type: NEGATIVELY_REGULATES description: SNX13 accelerates GTP hydrolysis on G alpha s, terminating its signal. - source: beta_gs target: beta_adenylyl_cyclase connection_type: POSITIVELY_REGULATES description: G alpha s-GTP stimulates adenylyl cyclase. - source: beta_adenylyl_cyclase target: beta_pka connection_type: PROVIDES_INPUT_FOR description: cAMP activates PKA. - source: beta_pka target: beta_adrb2_gi_switch connection_type: POSITIVELY_REGULATES description: >- PKA phosphorylation of ADRB2 uncouples it from Gs (heterologous desensitization) and switches it to Gi. evidence: - source_id: PMID:9363896 statement: PKA-mediated receptor phosphorylation both uncouples ADRB2 from Gs and switches it to Gi. supporting_text: >- Our results demonstrate that a mechanism previously shown to mediate uncoupling of the beta2-adrenergic receptor from Gs and thus heterologous desensitization (PKA-mediated receptor phosphorylation), also serves to 'switch' coupling of this receptor from Gs to Gi - source: beta_adrb2_gi_switch target: beta_adenylyl_cyclase connection_type: NEGATIVELY_REGULATES description: Gi-coupled ADRB2 inhibits adenylyl cyclase (GO:0071881). - source: beta_termination target: beta_receptors connection_type: NEGATIVELY_REGULATES description: GRK phosphorylation and beta-arrestin binding desensitize and internalize the receptors.