Beta-adrenergic receptor signaling — epinephrine acting through ADRB1/ADRB2, Gs, adenylyl cyclase/cAMP, PKA-dependent Gi switching, and GRK/beta-arrestin desensitization

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.

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.