id: MODULE:crh_receptor_signaling title: Corticotropin-releasing hormone receptor signaling — CRH and urocortins acting through CRHR1/CRHR2, Gs, adenylyl cyclase/cAMP, and GRK/beta-arrestin desensitization description: >- 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. status: DRAFT scope: CONCRETE references: - id: PMID:11329063 title: Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Hsu & Hsueh, Nat Med 2001). Stresscopin and stresscopin-related peptide are the UniProt alternative names of UCN3 (Q969E3) and UCN2 (Q96RP3); the paper is the IDA source for their neuropeptide hormone activity in GOA. Abstract only. - id: PMID:1846945 title: Cloning and characterization of the cDNAs for human and rat corticotropin releasing factor-binding proteins. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Potter et al., Nature 1991); IDA source for CRHBP receptor ligand inhibitor activity in GOA. Abstract only. - id: PMID:11247813 title: "GRK3 mediates desensitization of CRF1 receptors: a potential mechanism regulating stress adaptation." reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified; antisense knockdown of GRK3 in human Y-79 cells reduces homologous CRHR1 desensitization. Abstract only. - id: PMID:16412099 title: Differential regulation of corticotropin releasing factor 1alpha receptor endocytosis and trafficking by beta-arrestins and Rab GTPases. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Holmes et al., J Neurochem 2006; one of the RGD diagram references). CRHR1 recruits beta-arrestin-2 selectively, and GRK3/GRK6 increase the association. Abstract only. evidence: - source_id: PW:0000493 title: corticotropin-releasing hormone signaling pathway statement: >- The module boundary and its gene products follow the RGD diagram for this Pathway Ontology term: the ligands Crh, Ucn, Ucn2 and Ucn3; the binding protein Crhbp associated with Crh and Ucn; the receptors Crhr1 and Crhr2 associated with Gnas; cAMP leading into the PKA signaling pathway; and Adrbk2 (GRK3) and Grk6 acting negatively on Crhr1 together with Arrb1 and Arrb2 (receptor desensitization, receptor-G protein uncoupling, receptor internalization). The record text states that CRH preferentially binds CRHR1, UCN1 binds either receptor and UCN2 and UCN3 bind CRHR2. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000493.yaml). - source_id: GO:0071376 title: cellular response to corticotropin-releasing hormone stimulus statement: >- The module is grounded in the GO cellular-response term recorded as the curated skos:closeMatch for PW:0000493 in the project's PW-GO mappings; GO has no CRH receptor signaling pathway term. The Gs/adenylyl cyclase arm is the GO process adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), which the CRH, urocortin and CRHR GO-CAMs use for the receptor, GNAS and ADCY6 activities. notes: >- 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. module: id: crh_receptor_signaling label: Corticotropin-releasing hormone receptor signaling module_type: SIGNALING_PATHWAY concepts: - preferred_term: cellular response to corticotropin-releasing hormone stimulus term: id: GO:0071376 label: cellular response to corticotropin-releasing hormone stimulus description: >- CRH/urocortin binding to CRHR1 or CRHR2 and the resulting Gs-adenylyl cyclase-cAMP-PKA response, 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: extracellular region term: id: GO:0005576 label: extracellular region description: The peptide ligands and CRHBP act extracellularly. - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane description: Receptors, Gs and the GRK/arrestin step act at the plasma membrane. parts: - order: 1 role: CRH-family peptide ligands node: id: crh_ligands label: CRH and urocortin ligands module_type: REGULATORY_STEP description: >- Secreted CRH-family peptides that activate CRHR1 and/or CRHR2; any one of them satisfies the step, and the receptor each one prefers is given by the variant-to-variant connections. variant_sets: - id: crh_family_ligands label: CRH-family ligands axis: ligand paralog selection: ONE_OR_MORE notes: >- CRH acts preferentially on CRHR1, UCN on both receptors, and UCN2 and UCN3 selectively on CRHR2 (PW:0000493 record text; PMID:11329063). variants: - id: crh_ligand_variant label: Corticotropin-releasing hormone (CRH) module_type: REGULATORY_STEP annotons: - id: crh_hormone label: CRH corticotropin-releasing hormone activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CRH term: id: UniProtKB:P06850 label: Corticotropin-releasing hormone function: preferred_term: corticotropin-releasing hormone activity term: id: GO:0017045 label: corticotropin-releasing hormone activity targets: - preferred_term: CRHR1 term: id: UniProtKB:P34998 label: Corticotropin-releasing hormone receptor 1 locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Hypothalamic stress hormone; preferential CRHR1 agonist. gocam_associations: - model: gomodel:69729a3800006407 activity: gomodel:69729a3800006407/69729a3800006439 title: Whole body adaptation to stress following activation of CRHR1 by CRH, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0017045). - id: ucn_ligand_variant label: Urocortin (UCN) module_type: REGULATORY_STEP annotons: - id: ucn_hormone label: UCN corticotropin-releasing hormone activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: UCN term: id: UniProtKB:P55089 label: Urocortin function: preferred_term: corticotropin-releasing hormone activity term: id: GO:0017045 label: corticotropin-releasing hormone activity targets: - preferred_term: CRHR1 term: id: UniProtKB:P34998 label: Corticotropin-releasing hormone receptor 1 - preferred_term: CRHR2 term: id: UniProtKB:Q13324 label: Corticotropin-releasing hormone receptor 2 locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Urocortin 1; activates either receptor. gocam_associations: - model: gomodel:69729a3800006846 activity: gomodel:69729a3800006846/69729a3800006876 title: Whole body adaptation to stress following activation of CRHR1 by UCN, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0017045), CRHR1 arm. - model: gomodel:69729a3800006901 activity: gomodel:69729a3800006901/69729a3800006931 title: Whole body adaptation to stress following activation of CRHR2 by UCN, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0017045), CRHR2 arm. - id: ucn2_ligand_variant label: Urocortin-2 (UCN2) module_type: REGULATORY_STEP annotons: - id: ucn2_hormone label: UCN2 neuropeptide hormone activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: UCN2 (stresscopin-related peptide) term: id: UniProtKB:Q96RP3 label: Urocortin-2 function: preferred_term: neuropeptide hormone activity term: id: GO:0005184 label: neuropeptide hormone activity targets: - preferred_term: CRHR2 term: id: UniProtKB:Q13324 label: Corticotropin-releasing hormone receptor 2 locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Selective CRHR2 ligand. evidence: - source_id: PMID:11329063 statement: >- Stresscopin-related peptide (UCN2) and stresscopin (UCN3) are specific ligands for CRHR2. supporting_text: >- We identified human stresscopin (SCP) and stresscopin-related peptide (SRP) as specific ligands for the type 2 CRH receptor. gocam_associations: - model: gomodel:69729a3800007354 activity: gomodel:69729a3800007354/69729a3800007384 title: Whole body adaptation to stress following activation of CRHR2 by UCN2, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0005184). - id: ucn3_ligand_variant label: Urocortin-3 (UCN3) module_type: REGULATORY_STEP annotons: - id: ucn3_hormone label: UCN3 neuropeptide hormone activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: UCN3 (stresscopin) term: id: UniProtKB:Q969E3 label: Urocortin-3 function: preferred_term: neuropeptide hormone activity term: id: GO:0005184 label: neuropeptide hormone activity targets: - preferred_term: CRHR2 term: id: UniProtKB:Q13324 label: Corticotropin-releasing hormone receptor 2 locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Selective CRHR2 ligand. evidence: - source_id: PMID:11329063 statement: Stresscopin (UCN3) is a specific CRHR2 ligand. supporting_text: >- We identified human stresscopin (SCP) and stresscopin-related peptide (SRP) as specific ligands for the type 2 CRH receptor. gocam_associations: - model: gomodel:69729a3800007299 activity: gomodel:69729a3800007299/69729a3800007329 title: Whole body adaptation to stress following activation of CRHR2 by UCN3, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0005184). - order: 2 role: ligand sequestration by CRH-binding protein (regulation) optional: true node: id: crhbp_sequestration label: CRHBP sequesters CRH and urocortin module_type: REGULATORY_STEP description: >- The circulating CRH-binding protein binds CRH (and UCN) and blocks their access to the receptors, so reducing ACTH release driven by CRH. annotons: - id: crhbp_ligand_inhibitor label: CRHBP receptor ligand inhibitor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CRHBP term: id: UniProtKB:P24387 label: Corticotropin-releasing hormone-binding protein function: preferred_term: receptor ligand inhibitor activity term: id: GO:0141069 label: receptor ligand inhibitor activity targets: - preferred_term: CRH term: id: UniProtKB:P06850 label: Corticotropin-releasing hormone - preferred_term: UCN term: id: UniProtKB:P55089 label: Urocortin locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Extracellular ligand trap; negative regulator of the ligand step. evidence: - source_id: PMID:1846945 statement: Recombinant CRHBP binds CRF and blocks its stimulation of ACTH release by pituitary cells. supporting_text: >- Both rat and human recombinant binding proteins inhibit CRF binding to a CRF antibody and inhibit CRF-induced ACTH release by pituitary cells in vitro. gocam_associations: - model: gomodel:69729a3800006465 activity: gomodel:69729a3800006465/69729a3800006520 title: CRHBP inhibits corticotropin-releasing hormone activity (CRH) (Human). description: Same gene and molecular function (GO:0141069). - order: 3 role: CRH receptor activation node: id: crh_receptors label: CRHR1 and CRHR2 receptors module_type: REGULATORY_STEP description: >- The two class B CRH receptors; either one, occupied by a CRH-family ligand, activates Gs. variant_sets: - id: crh_receptor_paralogs label: CRH receptors axis: receptor paralog selection: ONE_OR_MORE notes: >- CRHR1 (pituitary, brain) carries the HPA-axis response to CRH; CRHR2 (brain and periphery) is the urocortin-selective receptor. Both couple predominantly to Gs. variants: - id: crhr1_variant label: CRH receptor 1 (CRHR1) module_type: REGULATORY_STEP annotons: - id: crhr1_receptor label: CRHR1 receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CRHR1 term: id: UniProtKB:P34998 label: Corticotropin-releasing hormone receptor 1 function: preferred_term: corticotrophin-releasing factor receptor activity term: id: GO:0015056 label: corticotrophin-releasing factor 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: Principal CRH receptor; activates Gs and is the GRK/arrestin target. gocam_associations: - model: gomodel:69729a3800006407 activity: gomodel:69729a3800006407/69729a3800006408 title: Whole body adaptation to stress following activation of CRHR1 by CRH, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0015056). - model: gomodel:69729a3800006846 activity: gomodel:69729a3800006846/69729a3800006847 title: Whole body adaptation to stress following activation of CRHR1 by UCN, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0015056). - id: crhr2_variant label: CRH receptor 2 (CRHR2) module_type: REGULATORY_STEP annotons: - id: crhr2_receptor label: CRHR2 receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CRHR2 term: id: UniProtKB:Q13324 label: Corticotropin-releasing hormone receptor 2 function: preferred_term: corticotrophin-releasing factor receptor activity term: id: GO:0015056 label: corticotrophin-releasing factor 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: Urocortin-selective CRH receptor; activates Gs. gocam_associations: - model: gomodel:69729a3800006901 activity: gomodel:69729a3800006901/69729a3800006902 title: Whole body adaptation to stress following activation of CRHR2 by UCN, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0015056). - model: gomodel:69729a3800006791 activity: gomodel:69729a3800006791/69729a3800006792 title: Whole body adaptation to stress following activation of CRHR2 by CRH, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0015056). - order: 4 role: Gs activation node: id: crh_gs label: Gs alpha (GNAS) activation module_type: REGULATORY_STEP description: >- Agonist-occupied CRHR1/CRHR2 act as guanine nucleotide exchange factors for Gs; GTP-bound G alpha s stimulates adenylyl cyclase. annotons: - id: crh_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 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 coupling both CRH receptors to adenylyl cyclase. gocam_associations: - model: gomodel:69729a3800006407 activity: gomodel:69729a3800006407/69729a3800006410 title: Whole body adaptation to stress following activation of CRHR1 by CRH, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0003925); the other CRH/UCN models repeat it. - model: gomodel:69729a3800006901 activity: gomodel:69729a3800006901/69729a3800006904 title: Whole body adaptation to stress following activation of CRHR2 by UCN, leading to signaling via G-alpha-s (Human) description: Same gene and molecular function (GO:0003925), CRHR2 arm. - order: 5 role: adenylyl cyclase produces cAMP node: id: crh_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 for CRH signalling. module_ref: gpcr_camp_pka_signaling#adenylyl_cyclase_activation - order: 6 role: PKA activation and CREB output node: id: crh_pka label: PKA activation and CREB phosphorylation description: >- Included by reference to the PKA/CREB step of the generic Gs-cAMP-PKA module. In corticotrophs CREB drives POMC transcription, an output outside this module. module_ref: gpcr_camp_pka_signaling#pka_creb_output - order: 7 role: receptor desensitization (termination) node: id: crh_termination label: GRK phosphorylation and beta-arrestin desensitization of CRHR1 module_type: REGULATORY_STEP description: >- GRK3 and GRK6 phosphorylate agonist-occupied CRHR1; beta-arrestins bind the phosphorylated receptor, uncouple it from Gs and drive its internalization. annotons: - id: crh_grk label: GRK3/GRK6 phosphorylation of CRHR1 participant: selector_type: FAMILY family: preferred_term: G protein-coupled receptor kinases GRK3 and GRK6 representative_members: - preferred_term: GRK3 term: id: UniProtKB:P35626 label: G protein-coupled receptor kinase 3 - preferred_term: GRK6 term: id: UniProtKB:P43250 label: G protein-coupled receptor kinase 6 function: preferred_term: G protein-coupled receptor kinase activity term: id: GO:0004703 label: G protein-coupled receptor kinase activity targets: - preferred_term: CRHR1 term: id: UniProtKB:P34998 label: Corticotropin-releasing hormone receptor 1 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 receptor, the first step of homologous desensitization. evidence: - source_id: PMID:11247813 statement: GRK3 knockdown reduces homologous desensitization of CRHR1 in human Y-79 cells. supporting_text: >- We conclude that GRK3 contributes importantly to the homologous desensitization of CRF1 receptors in Y-79 cells, a brain-derived cell line. gocam_associations: - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004492 title: Desensitization of C5AR1-mediated signaling following phosphorylation by GRK2 or GRK3 (Human). description: >- GRK3 with the same molecular function (GO:0004703) and process (GO:0002029), modelled on C5AR1 rather than a CRH receptor. - id: crh_arrestin label: Beta-arrestin uncoupling and internalization of CRHR1 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: CRHR1 term: id: UniProtKB:P34998 label: Corticotropin-releasing hormone receptor 1 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 CRHR1, block Gs coupling and target the receptor to endocytosis; CRHR1 recruits beta-arrestin-2 selectively. evidence: - source_id: PMID:16412099 statement: >- CRHR1 activation selectively recruits beta-arrestin-2, and GRK3/GRK6 increase the beta-arrestin-2-CRHR1 association. supporting_text: >- we demonstrated that beta-arrestin2 association with CRF1alpha receptor was increased in cells transfected with G protein-coupled receptor kinase (GRK)3 and GRK6 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. - 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. connections: - source: crh_ligand_variant target: crhr1_variant connection_type: POSITIVELY_REGULATES description: CRH preferentially activates CRHR1. - source: ucn_ligand_variant target: crhr1_variant connection_type: POSITIVELY_REGULATES description: UCN activates CRHR1. - source: ucn_ligand_variant target: crhr2_variant connection_type: POSITIVELY_REGULATES description: UCN activates CRHR2. - source: ucn2_ligand_variant target: crhr2_variant connection_type: POSITIVELY_REGULATES description: UCN2 selectively activates CRHR2. - source: ucn3_ligand_variant target: crhr2_variant connection_type: POSITIVELY_REGULATES description: UCN3 selectively activates CRHR2. - source: crhbp_sequestration target: crh_ligands connection_type: NEGATIVELY_REGULATES description: CRHBP binds CRH and UCN and prevents them from activating the receptors. - source: crh_receptors target: crh_gs connection_type: POSITIVELY_REGULATES description: Occupied CRHR1/CRHR2 activate Gs. - source: crh_gs target: crh_adenylyl_cyclase connection_type: POSITIVELY_REGULATES description: G alpha s-GTP stimulates adenylyl cyclase. - source: crh_adenylyl_cyclase target: crh_pka connection_type: PROVIDES_INPUT_FOR description: cAMP activates PKA. - source: crh_termination target: crh_receptors connection_type: NEGATIVELY_REGULATES description: GRK phosphorylation and beta-arrestin binding desensitize and internalize CRHR1.