Corticotropin-releasing hormone receptor signaling — CRH and urocortins acting through CRHR1/CRHR2, Gs, adenylyl cyclase/cAMP, and GRK/beta-arrestin desensitization

Corticotropin-releasing hormone (CRH) and the related urocortins (UCN, UCN2, UCN3) are secreted peptide hormones that signal through two class B G protein-coupled receptors, CRHR1 and CRHR2. The receptors differ in ligand selectivity: CRH acts preferentially on CRHR1, urocortin 1 (UCN) activates either receptor, and urocortin 2 (UCN2) and urocortin 3 (UCN3) are selective CRHR2 ligands. Agonist-occupied receptors activate the stimulatory G alpha subunit (GNAS), which stimulates adenylyl cyclase; the resulting cAMP activates protein kinase A (PKA), which phosphorylates cytoplasmic and nuclear targets including the transcription factor CREB. In the anterior pituitary this cascade drives adrenocorticotropin (ACTH) release, the first step of the hypothalamic-pituitary-adrenal stress axis. A circulating CRH-binding protein (CRHBP) sequesters CRH and urocortin and inhibits their action on the receptors. Signalling is terminated when G protein-coupled receptor kinases (GRK3, GRK6) phosphorylate agonist-occupied CRHR1, promoting beta-arrestin (ARRB1, ARRB2) binding, which uncouples the receptor from Gs and drives its internalization.

Derived from the RGD Pathway Ontology diagram PW:0000493 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 rather than re-modelled) -> termination by GRK phosphorylation and beta-arrestin binding. Molecular functions were taken from each protein's experimental GO annotations in QuickGO (CRH and UCN GO:0017045 IDA; UCN2 and UCN3 GO:0005184 IDA PMID:11329063; CRHBP GO:0141069 IDA PMID:1846945; CRHR1 and CRHR2 GO:0015056 IDA; GNAS P63092 GO:0003925 IDA; GRK3 and GRK6 GO:0004703 IDA; ARRB1 and ARRB2 GO:0030674 IDA), verified against go-basic (releases/2026-07-26). GO spells the receptor term "corticotrophin-releasing factor receptor activity"; the label is kept verbatim. Ligands. CRH and the three urocortins are given hormone activity only (the GO corticotropin-releasing hormone activity and neuropeptide hormone activity terms, both is_a hormone activity), with no process annotation, following the substrate-versus- participant rule: the peptide is the signal, the receptors and downstream enzymes do the work of the pathway. The ligands are a ONE_OR_MORE variant set, and receptor selectivity is made explicit as variant-to-variant connections (CRH -> CRHR1; UCN -> CRHR1 and CRHR2; UCN2 and UCN3 -> CRHR2). CRH also activates CRHR2 at lower potency and the production GO-CAM gomodel:69729a3800006791 models CRH on CRHR2; the RGD text says CRH binds CRHR1 "preferentially", so that edge is recorded here in prose only. Pro-CRH processing and secretion (modelled in gomodel:69729a3800006347) are ligand supply, outside the module. CRHBP is modelled as a ligand-sequestering binding protein that negatively regulates the ligand step (GO:0141069 receptor ligand inhibitor activity, targets CRH and UCN), as in gomodel:69729a3800006465. It is not a pathway participant in the Gs sense; it acts in the extracellular space by binding the hormone. Shared steps by reference. The Gs step is modelled locally (GNAS P63092, the Gs-alpha short isoform accession used by the CRH/UCN GO-CAMs) because it is the receptor-specific coupling RGD draws; adenylyl cyclase and PKA/CREB are module_refs to the generic modules/gpcr_camp_pka_signaling.yaml nodes. The RGD diagram names no adenylyl cyclase isoform; the GO-CAMs use ADCY6 and the generic module uses ADCY5 as its exemplar, so no isoform is asserted here. The repository GNAS gene review (genes/human/GNAS) is for the NESP55 accession O95467, not Gs alpha, and does not cover this activity. Termination. RGD links Adrbk2 (human GRK3) and Grk6 negatively to Crhr1, and Arrb1/Arrb2 to Crhr1. GRK3 antisense reduces homologous CRHR1 desensitization (PMID:11247813) and GRK3/GRK6 increase CRHR1-beta-arrestin-2 association (PMID:16412099), which also reports selective beta-arrestin-2 recruitment; ARRB1 is kept beside ARRB2 because RGD links both and both carry the adaptor activity, but the evidence for CRHR1 favours ARRB2. GRK2 participation reported in pituitary corticotroph cells is outside the RGD gene list and is not modelled. No termination step is asserted for CRHR2. Outside the module: the ACTH (POMC) output and the downstream melanocortin and glucocorticoid axes (RGD links PW:0000365 melanocortin system pathway), CRH neuron activation by stress, and the cardiovascular outputs of the urocortins. Possible Gq or Gi coupling, which the RGD text mentions as unresolved, is not modelled. GO-CAM grounding. Each ligand, receptor and GNAS annoton is linked to the matching activity in the human Reactome-derived CRH/UCN models (gomodel:69729a3800006407, ...006791, ...006846, ...006901, ...007299, ...007354) and CRHBP to gomodel:69729a3800006465; the GRK and arrestin annotons are linked to the generic GRK2/GRK3/arrestin desensitization model gomodel:67f85f2b00004426 (for C5AR1), which shares gene and molecular function but not the receptor. Of the module's gene products only GNAS (a different accession) has a gene review; reviews for the rest are curation follow-up for the project plan.