id: MODULE:glucagon_receptor_signaling title: Glucagon receptor signaling — glucagon acting through GCGR, Gs, adenylyl cyclase 5/6 and cAMP/PKA, with GRK/beta-arrestin desensitization description: >- Glucagon is the counter-regulatory hormone to insulin: released from pancreatic alpha cells when blood glucose falls, it acts chiefly on liver and kidney through the glucagon receptor (GCGR), a class B G protein-coupled receptor. Agonist-occupied GCGR acts as a guanine nucleotide exchange factor for the stimulatory G protein; GTP-bound G alpha s (GNAS) activates the membrane adenylyl cyclases ADCY5 and ADCY6, raising cAMP and activating protein kinase A (PKA). PKA then drives the hepatic glucose-output programme — activation of glycogenolysis, inhibition of glycogen synthesis and glycolysis, and promotion of gluconeogenesis — which lies downstream of this module. Glucagon itself is one of several peptides cut from the preproglucagon precursor encoded by GCG; the convertase that makes glucagon in alpha cells is part of hormone processing rather than of receptor signalling. As for the other Gs-coupled hormone receptors, signalling is limited by G protein-coupled receptor kinase phosphorylation of the occupied receptor and subsequent beta-arrestin binding. status: DRAFT scope: CONCRETE references: - id: PMID:8384375 title: Expression cloning and signaling properties of the rat glucagon receptor. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Jelinek et al., Science 1993; RGD diagram reference). The cloned glucagon receptor binds glucagon and raises cAMP. Abstract only. - id: PMID:2163110 title: "beta-Arrestin: a protein that regulates beta-adrenergic receptor function." reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified (Lohse et al., Science 1990); cited for the generic GRK-arrestin desensitization mechanism, which was established on beta-adrenergic receptors, not on GCGR. Abstract only. evidence: - source_id: PW:0000676 title: glucagon signaling pathway statement: >- The module boundary and its gene products follow the RGD diagram for this Pathway Ontology term: Gcg associated with Gcgr; Gcgr associated with Gnas; Gnas leading to Adcy5 and Adcy6; ATP converted to cAMP; and cAMP feeding the PKA signaling pathway, which then drives glycogen degradation and gluconeogenesis and inhibits glycolysis and glycogen biosynthesis. The record text states that glucagon is processed from proglucagon by prohormone convertase 2 in pancreatic alpha cells and that binding of glucagon activates primarily Gs alpha. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000676.yaml). - source_id: GO:0071377 title: cellular response to glucagon stimulus statement: >- The module is grounded in the GO cellular-response term recorded as the curated skos:closeMatch for PW:0000676 in the project's PW-GO mappings; GO has no glucagon receptor signaling pathway term. It is also the process of the mouse GO-CAM gomodel:636d9ce800000147 ("Cellular response to glucagon stimulus"), whose activities are the mouse orthologs of this module's receptor, G protein, cyclase and PKA steps. notes: >- Derived from the RGD Pathway Ontology diagram PW:0000676 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 -> 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 GCG gene review, and verified against go-basic (releases/2026-07-26): GCGR GO:0004967 IDA; GNAS P63092 GO:0003925 IDA; ADCY5 GO:0004016 EXP/IDA; ADCY6 GO:0004016 EXP/IDA; GRK2 GO:0004703 IDA; ARRB1/ARRB2 GO:0030674 IDA. Ligand. The ligand annoton is the glucagon peptide, the GCG cleavage product UniProtKB:P01275-PRO_0000011256, with hormone activity only and no process role, as in the human GO-CAM gomodel:68d5ebd600000298 and following the substrate-versus-participant rule. The completed GCG gene review (genes/human/GCG, P01275) carries GO:0005179 hormone activity as a core function, so the claim is consistent with it; the review is keyed to the parent accession, which is why the module validator reports one CONTEXT_REQUIRED warning for this annoton: the chain-level assertion cannot be matched automatically to the gene-level review. The warning is expected and the claim is the review's own core function. Processing of preproglucagon by PCSK2 in alpha cells, and the alternative PCSK1 products (GLP-1, GLP-2, oxyntomodulin) with their own receptors, are hormone production and separate pathways, outside the module. Cyclase modelled locally. Unlike the three sibling modules, RGD names the cyclase isoforms here (Adcy5 and Adcy6), so the cyclase step is modelled as a ONE_OR_MORE variant set of those two human enzymes rather than taken by reference from modules/gpcr_camp_pka_signaling.yaml; the PKA step is still a module_ref to that module. The mouse GO-CAM for this process uses Adcy8, a third isoform that RGD does not draw and that is not modelled here. Outputs out of scope. Hepatic glycogenolysis, gluconeogenesis and the inhibition of glycolysis and glycogen synthesis are RGD subpathways (PW:0000534, PW:0000641, PW:0000640, PW:0000532) reached through PKA; they are downstream outputs, not parts of receptor signalling, and are kept out of the module. Gq coupling, which the RGD text raises as possible and for which the cloned receptor's calcium response (PMID:8384375) is the evidence, is not asserted. Termination. RGD's glucagon diagram draws no GRK or arrestin, but the brief for this batch models termination in all four modules. The step here is therefore marked optional and grounded only on the generic mechanism (GRK2 phosphorylation of the occupied receptor and beta-arrestin binding, PMID:2163110, established on beta-adrenergic receptors); no publication or cached GO-CAM tying GRK2 or an arrestin to GCGR was found, which is recorded as a knowledge gap rather than asserted. GCGR is not among the receptors in the GRK/arrestin desensitization model gomodel:67f85f2b00004426 either, so that model is linked for gene and function only. GO-CAM grounding. Glucagon, GCGR and GNAS are linked to the human Gs model gomodel:68d5ebd600000298, and the receptor, G protein and ligand steps also to the mouse "Cellular response to glucagon stimulus" model gomodel:636d9ce800000147 where the orthologous gene carries the same molecular function (Gcgr GO:0004967, Gnas GO:0003925, Gcg GO:0048018 receptor ligand activity, the parent of which the human model types as GO:0005179 hormone activity). The second candidate model, gomodel:65288b2200000062, is the GPR174 signaling pathway: it shares only the generic GNAS and ADCY6 activities and no glucagon-specific gene, so it is not linked. A second human model, gomodel:68d5ebd600000330, gives GCGR a Gi-coupled arm; that arm is not modelled here for the same reason as the Gq route. knowledge_gaps: - gap_statement: >- Which G protein-coupled receptor kinase phosphorylates agonist-occupied GCGR, and whether beta-arrestin-1 or beta-arrestin-2 mediates its desensitization and internalization, has not been established. boundary: >- The termination part is optional and rests on the generic GRK/arrestin mechanism; no GCGR-specific kinase or arrestin is asserted. gap_kind: - BIOLOGY status: OPEN significance: >- Determines whether glucagon-receptor desensitization can be targeted separately from receptor antagonism in the treatment of diabetes. resolution: >- GRK-isoform knockout or knockdown with phosphosite mapping of GCGR, and arrestin recruitment assays with ARRB1 and ARRB2 individually deleted. module: id: glucagon_receptor_signaling label: Glucagon receptor signaling module_type: SIGNALING_PATHWAY concepts: - preferred_term: cellular response to glucagon stimulus term: id: GO:0071377 label: cellular response to glucagon stimulus description: >- Glucagon binding to GCGR and the resulting Gs-adenylyl cyclase-cAMP-PKA response in liver and kidney, with GRK/beta-arrestin termination. 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: extracellular region term: id: GO:0005576 label: extracellular region description: Glucagon is secreted and acts on the receptor from outside the cell. - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane description: GCGR, Gs, the adenylyl cyclases and the GRK/arrestin step act at the plasma membrane. parts: - order: 1 role: glucagon ligand node: id: glucagon_ligand label: Glucagon module_type: REGULATORY_STEP description: >- The glucagon peptide released from pancreatic alpha cells, one of the cleavage products of preproglucagon; its only asserted function is hormone activity. annotons: - id: glucagon_hormone label: Glucagon hormone activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GCG (glucagon peptide) term: id: UniProtKB:P01275-PRO_0000011256 label: Glucagon function: preferred_term: hormone activity term: id: GO:0005179 label: hormone activity targets: - preferred_term: GCGR term: id: UniProtKB:P47871 label: Glucagon receptor locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Counter-regulatory glucose-raising hormone; the signal, not a catalytic participant. Its production from preproglucagon by PCSK2 is outside the module. gocam_associations: - model: gomodel:68d5ebd600000298 activity: gomodel:68d5ebd600000298/68d5ebd600000308 title: GCGR-mediated signaling via G-alpha-s following activation by glucagon (Human) description: Same cleavage product and molecular function (GO:0005179). - model: gomodel:636d9ce800000147 activity: gomodel:636d9ce800000147/636d9ce800000154 title: Cellular response to glucagon stimulus (Mouse) description: >- Mouse Gcg in the same role, typed with GO:0048018 receptor ligand activity, the parent of hormone activity. - order: 2 role: glucagon receptor activation node: id: glucagon_receptor label: GCGR glucagon receptor module_type: REGULATORY_STEP description: >- Glucagon-occupied GCGR acts as a guanine nucleotide exchange factor for Gs; the receptor is expressed predominantly in liver and kidney. annotons: - id: gcgr_receptor label: GCGR glucagon receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GCGR term: id: UniProtKB:P47871 label: Glucagon receptor function: preferred_term: glucagon receptor activity term: id: GO:0004967 label: glucagon receptor activity processes: - preferred_term: adenylate cyclase-activating G protein-coupled receptor signaling pathway term: id: GO:0007189 label: adenylate cyclase-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Class B receptor for glucagon; activates Gs. evidence: - source_id: PMID:8384375 statement: The cloned glucagon receptor binds glucagon and raises intracellular cAMP. supporting_text: >- The cloned receptor bound glucagon and caused an increase in the intracellular concentration of adenosine 3', 5'-monophosphate (cAMP). gocam_associations: - model: gomodel:68d5ebd600000298 activity: gomodel:68d5ebd600000298/68d5ebd600000299 title: GCGR-mediated signaling via G-alpha-s following activation by glucagon (Human) description: Same gene, molecular function (GO:0004967) and process (GO:0007189). - model: gomodel:636d9ce800000147 activity: gomodel:636d9ce800000147/636d9ce800000181 title: Cellular response to glucagon stimulus (Mouse) description: Mouse Gcgr with the same molecular function (GO:0004967). - order: 3 role: Gs activation node: id: glucagon_gs label: Gs alpha (GNAS) activation module_type: REGULATORY_STEP description: GTP-bound G alpha s dissociates from the receptor and stimulates adenylyl cyclase. annotons: - id: glucagon_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 targets: - preferred_term: ADCY5 term: id: UniProtKB:O95622 label: Adenylate cyclase type 5 - preferred_term: ADCY6 term: id: UniProtKB:O43306 label: Adenylate cyclase type 6 processes: - preferred_term: adenylate cyclase-activating G protein-coupled receptor signaling pathway term: id: GO:0007189 label: adenylate cyclase-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Stimulatory G alpha subunit; RGD draws Gnas acting on both Adcy5 and Adcy6. gocam_associations: - model: gomodel:68d5ebd600000298 activity: gomodel:68d5ebd600000298/68d5ebd600000318 title: GCGR-mediated signaling via G-alpha-s following activation by glucagon (Human) description: Same gene and molecular function (GO:0003925). - model: gomodel:636d9ce800000147 activity: gomodel:636d9ce800000147/636d9ce800000174 title: Cellular response to glucagon stimulus (Mouse) description: Mouse Gnas with the same molecular function (GO:0003925). - order: 4 role: cAMP synthesis by adenylyl cyclase 5 or 6 node: id: glucagon_adenylyl_cyclase label: ADCY5/ADCY6 produce cAMP module_type: REACTION description: >- G alpha s-GTP activates the membrane adenylyl cyclases named by the RGD diagram, which convert ATP to cAMP. variant_sets: - id: glucagon_cyclase_isoforms label: Adenylyl cyclase isoforms axis: enzyme isoform selection: ONE_OR_MORE notes: >- RGD draws Gnas acting on both Adcy5 and Adcy6; the record text notes that the identity of the cyclase isoforms is only partly resolved, so either satisfies the step. variants: - id: adcy5_variant label: Adenylate cyclase type 5 (ADCY5) module_type: REACTION annotons: - id: adcy5_activity label: ADCY5 adenylate cyclase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ADCY5 term: id: UniProtKB:O95622 label: Adenylate cyclase type 5 function: preferred_term: adenylate cyclase activity term: id: GO:0004016 label: adenylate cyclase activity products: - preferred_term: cyclic AMP processes: - preferred_term: adenylate cyclase-activating G protein-coupled receptor signaling pathway term: id: GO:0007189 label: adenylate cyclase-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: One of the two cyclase isoforms RGD assigns to this pathway. - id: adcy6_variant label: Adenylate cyclase type 6 (ADCY6) module_type: REACTION annotons: - id: adcy6_activity label: ADCY6 adenylate cyclase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ADCY6 term: id: UniProtKB:O43306 label: Adenylate cyclase type 6 function: preferred_term: adenylate cyclase activity term: id: GO:0004016 label: adenylate cyclase activity products: - preferred_term: cyclic AMP processes: - preferred_term: adenylate cyclase-activating G protein-coupled receptor signaling pathway term: id: GO:0007189 label: adenylate cyclase-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The cyclase isoform used by the human GCGR and other Gs-coupled hormone receptor GO-CAMs. - order: 5 role: PKA activation and output node: id: glucagon_pka label: PKA activation and substrate phosphorylation description: >- Included by reference to the PKA/CREB step of the generic Gs-cAMP-PKA module. The hepatic glycogenolysis, gluconeogenesis and glycolysis outputs of PKA are outside this module. module_ref: gpcr_camp_pka_signaling#pka_creb_output - order: 6 role: receptor desensitization (termination) optional: true node: id: glucagon_termination label: GRK phosphorylation and beta-arrestin desensitization module_type: REGULATORY_STEP description: >- The generic termination step for a Gs-coupled receptor: GRK phosphorylation of the occupied receptor followed by beta-arrestin binding, which blocks G protein coupling and drives internalization. No GCGR-specific kinase or arrestin has been established, so the step is optional and the receptor target is not asserted. annotons: - id: glucagon_grk label: GRK phosphorylation of the occupied receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GRK2 term: id: UniProtKB:P25098 label: G protein-coupled receptor kinase 2 function: preferred_term: G protein-coupled receptor kinase activity term: id: GO:0004703 label: G protein-coupled receptor kinase activity 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: >- The best-characterized GRK of Gs-coupled receptors, used here as the exemplar of the step; its action on GCGR itself is a knowledge gap. 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; GCGR is not in the model. - id: glucagon_arrestin label: Beta-arrestin uncoupling and internalization 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 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 and block G protein coupling; which arrestin acts on GCGR is unknown. evidence: - source_id: PMID:2163110 statement: >- Beta-arrestin inhibits signalling by receptors phosphorylated by the G protein-coupled receptor kinase, the generic desensitization mechanism. supporting_text: >- It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors. gocam_associations: - 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: glucagon_ligand target: glucagon_receptor connection_type: POSITIVELY_REGULATES description: Glucagon binding activates GCGR. - source: glucagon_receptor target: glucagon_gs connection_type: POSITIVELY_REGULATES description: Occupied GCGR acts as a GEF for Gs. - source: glucagon_gs target: glucagon_adenylyl_cyclase connection_type: POSITIVELY_REGULATES description: G alpha s-GTP stimulates ADCY5/ADCY6. - source: glucagon_adenylyl_cyclase target: glucagon_pka connection_type: PROVIDES_INPUT_FOR description: cAMP produced by the cyclases activates PKA. - source: glucagon_termination target: glucagon_receptor connection_type: NEGATIVELY_REGULATES description: >- GRK phosphorylation and beta-arrestin binding desensitize and internalize the receptor; the GCGR-specific kinase and arrestin are not established.