id: MODULE:pth_receptor_signaling title: Parathyroid hormone receptor signaling — PTH acting through PTH1R, dual Gs/adenylyl cyclase and Gq/PLC coupling, NHERF/ezrin scaffold control of coupling, and GRK2/beta-arrestin desensitization description: >- Parathyroid hormone (PTH), secreted by the parathyroid glands when blood calcium falls, acts on kidney and bone through the parathyroid hormone 1 receptor (PTH1R), a class B G protein-coupled receptor that is also activated by PTH-related protein. A single PTH1R couples to two G protein routes: the stimulatory G alpha s (GNAS), which activates adenylyl cyclase, cAMP production and protein kinase A, and is the main route; and G alpha q/11, which activates phospholipase C beta, producing inositol trisphosphate (calcium release) and diacylglycerol (protein kinase C). The balance between the two is set by scaffold proteins at the receptor's carboxy-terminal tail. The PDZ-domain scaffolds NHERF1 and NHERF2 bind the PTH1R carboxy terminus; NHERF2 simultaneously binds phospholipase C beta 1, biasing PTH1R toward phospholipase C signalling and inhibiting adenylyl cyclase through Gi/o, and NHERF1 likewise enables PTH-stimulated calcium signalling. Ezrin, an actin-membrane linker, binds both PTH1R and NHERF1 and supports apical PTH1R localization and signalling in renal proximal tubule cells. Signalling is terminated when GRK2 phosphorylates the agonist-occupied receptor and beta-arrestins (ARRB1, ARRB2) bind it, uncoupling it from G proteins and driving its dynamin-dependent endocytosis. status: DRAFT scope: CONCRETE references: - id: PMID:1313566 title: "Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium." reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Abou-Samra et al., PNAS 1992); a single cloned rat/opossum PTH1R stimulates both adenylate cyclase and phospholipase C. Abstract only. - id: PMID:21777186 title: The parathyroid hormone receptorsome and the potential for therapeutic intervention. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified review (Mahon, Curr Drug Targets 2012; RGD diagram reference RGD:7207465). Used for multi-G-protein coupling (including Gs) and the PTH1R-ezrin-NHERF1 receptorsome. Abstract only. - id: PMID:12075354 title: Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Mahon et al., Nature 2002); NHERF1 and NHERF2 bind the PTH1R carboxy terminus, and NHERF2 tethers phospholipase C beta 1 so that PTH shifts the receptor toward phospholipase C and Gi/o. Abstract only. - id: PMID:20843475 title: EBP50 inhibits the anti-mitogenic action of the parathyroid hormone type 1 receptor in vascular smooth muscle cells. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified (Song et al., J Mol Cell Cardiol 2010); full text cached. Cited for NHERF1/EBP50 conferring calcium signalling on PTH1R in a vascular smooth muscle line, the NHERF1 counterpart of the NHERF2 result. - id: PMID:19608645 title: The parathyroid hormone 1 receptor directly binds to the FERM domain of ezrin, an interaction that supports apical receptor localization and signaling in LLC-PK1 cells. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Mahon, Mol Endocrinol 2009); direct PTH1R-ezrin FERM interaction supporting apical receptor localization and signalling. Abstract only. - id: PMID:9849959 title: Identification of phosphorylation sites in the G protein-coupled receptor for parathyroid hormone. Receptor phosphorylation is not required for agonist-induced internalization. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Malecz et al., Mol Endocrinol 1998); GRK2, not GRK3, enhances agonist-stimulated PTH1R phosphorylation, and internalization does not require it. Abstract only. - id: PMID:12920119 title: Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50). reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Sneddon et al., JBC 2003); PTH1R undergoes beta-arrestin/ dynamin-mediated endocytosis with active PTH, while NHERF1 gates an arrestin-independent route. Abstract only. evidence: - source_id: PW:0001135 title: parathyroid hormone signaling pathway statement: >- The module boundary and its gene products follow the RGD diagram for this Pathway Ontology term: Pth associated with Pth1r; Pth1r feeding both the Galphas family and the Galphaq family G protein signaling pathways, giving cAMP/PKA and DAG/IP3 via PLC; Adrbk1 (GRK2) acting negatively on Pth1r with Arrb1 and Arrb2 associated with it; Ezr associated with both Pth1r and Slc9a3r1; and Slc9a3r1 (NHERF1) and Slc9a3r2 (NHERF2) associated with Pth1r. The record text states that the NHERF interaction biases the receptor between the two G protein routes, promoting Galphaq and either inhibiting or not affecting Galphas. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0001135.yaml). - source_id: GO:0071374 title: cellular response to parathyroid hormone stimulus statement: >- The module is grounded in the GO cellular-response term recorded as the curated skos:closeMatch for PW:0001135 in the project's PW-GO mappings; GO has no PTH receptor signaling pathway term. The Gs arm is the GO process adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), used by the human PTH1R GO-CAM gomodel:67c10cc400004508. notes: >- Derived from the RGD Pathway Ontology diagram PW:0001135 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 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 (PTH GO:0005179 IDA/IMP; PTH1R GO:0004991 IDA; GNAS P63092 GO:0003925 IDA; GRK2 GO:0004703 IDA; ARRB1/ARRB2 GO:0030674 IDA; EZR GO:0019904 IPI), verified against go-basic (releases/2026-07-26). The NHERF scaffolds are given GO:0030674 protein-macromolecule adaptor activity, the protein-protein counterpart of their GOA GO:0043495 protein-membrane adaptor activity (IBA): the activity modelled here is tethering PTH1R and phospholipase C beta 1 to each other. GO:0030165 PDZ domain binding, which NHERF1 carries by IPI, would say the reverse of what happens (NHERF's own PDZ domains bind the receptor's PDZ-binding motif). Ezrin keeps its GOA GO:0019904 protein domain specific binding (IPI): it too links PTH1R and NHERF1, but it has no adaptor-activity row in GOA, so the module keeps its experimental binding row rather than inferring an adaptor activity for it. Ligand. PTH carries hormone activity only, with no process role, following the substrate-versus-participant rule: the peptide is the signal and the receptor and downstream enzymes do the work. PTH secretion and its control by the calcium-sensing receptor (RGD links PW:0001141) are upstream of the module. PTHLH (PTHrP), the second PTH1R agonist, is not on the RGD gene list and is mentioned in prose only; the human GO-CAM gomodel:67c10cc400004549 models that arm. GNAS added. GNAS is not on RGD's curated gene list for PW:0001135 (RGD represents the Gs step as a link to the pathway PW:0000227) but the Gs step cannot be modelled without it, so it is added with the same grounding as the sibling modules: UniProtKB:P63092 with GO:0003925 G protein activity (IDA), and the activity gomodel:67c10cc400004508/67c10cc400004511 in the human PTH1R Gs GO-CAM, which places GNAS between PTH1R and ADCY6. The repository GNAS gene review is for the NESP55 accession O95467, not Gs alpha. Dual coupling. A single cloned PTH1R stimulates both adenylate cyclase and phospholipase C (PMID:1313566), and the receptor couples to several G protein classes including Gs and Gq/11 (PMID:21777186). The Gs arm is modelled locally through GNAS and then by reference to the generic cAMP/PKA module; the Gq arm is a module_ref to the PLC beta step of modules/gpcr_plc_calcium_pkc_signaling.yaml rather than re-modelled, since RGD represents it as a link to PW:0000229. The two arms are a ONE_OR_MORE variant set on the receptor node, because PTH1R can use either and the scaffold state decides which dominates. Gi/o and G12/13 coupling, which PMID:21777186 also lists, is not modelled: RGD draws neither, and the only Gi evidence used here is the NHERF2-dependent adenylyl cyclase inhibition reported in PMID:12075354, which is recorded on the scaffold regulation rather than as a separate G protein step. NHERF/ezrin scaffold as regulation. NHERF1 and NHERF2 bind the PTH1R PDZ motif; NHERF2 additionally binds PLC beta 1 so PTH activates PLC beta and inhibits adenylyl cyclase through Gi/o (PMID:12075354), and NHERF1/EBP50 confers PTH-stimulated calcium signalling on cells that otherwise show only cAMP (PMID:20843475). Ezrin binds the PTH1R carboxy-terminal tail through its FERM domain and binds NHERF1, and a dominant-negative ezrin selectively disrupts apical PTH1R signalling (PMID:19608645; the receptorsome is reviewed in PMID:21777186). The three are therefore modelled as one regulatory part that positively regulates the Gq arm and negatively regulates the Gs arm, with protein-macromolecule adaptor activity (NHERF1/NHERF2) and protein domain specific binding (EZR) as the molecular functions rather than any catalytic or receptor activity. The downstream phosphate-transport output of the complex (SLC34A1/NPT2a retrieval, RGD link PW:0001183) and the bone and renal calcium-handling outputs are outside the module, so SLC34A1 is not a member even though RGD lists it. Termination. GRK2 (RGD Adrbk1) enhances agonist-dependent PTH1R phosphorylation whereas GRK3 does not (PMID:9849959), so only GRK2 is modelled, and that paper's finding that phosphorylation is not required for internalization is recorded as a caveat on the termination node: GRK phosphorylation drives the uncoupling step, not endocytosis per se. Active PTH drives beta-arrestin/dynamin-mediated PTH1R endocytosis (PMID:12920119), which also shows an arrestin-independent route gated by NHERF1 — a second, deliberate link between the scaffold part and termination, recorded in the connection description. GO-CAM grounding. PTH, PTH1R and GNAS are linked to the human PTH1R Gs model gomodel:67c10cc400004508; the GRK and arrestin annotons to the GRK/arrestin desensitization model gomodel:67f85f2b00004426 (built for C5AR1, so gene and function match but not the receptor). No cached GO-CAM covers the NHERF/ezrin scaffold. None of this module's gene products has a gene review yet (the GNAS review is a different accession); those are curation follow-up for the project plan. module: id: pth_receptor_signaling label: Parathyroid hormone receptor signaling module_type: SIGNALING_PATHWAY concepts: - preferred_term: cellular response to parathyroid hormone stimulus term: id: GO:0071374 label: cellular response to parathyroid hormone stimulus description: >- PTH binding to PTH1R and the resulting Gs-adenylyl cyclase-cAMP-PKA and Gq-PLC responses, biased by the NHERF/ezrin scaffold and terminated by GRK2/beta-arrestin. 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: PTH circulates and acts on the receptor from outside the cell. - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane description: >- PTH1R, Gs and the GRK/arrestin step act at the plasma membrane; in renal proximal tubule the scaffolded receptor pool is apical. parts: - order: 1 role: PTH ligand node: id: pth_ligand label: Parathyroid hormone module_type: REGULATORY_STEP description: >- Secreted parathyroid hormone, the agonist of PTH1R; its only asserted function is hormone activity. annotons: - id: pth_hormone label: PTH hormone activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTH term: id: UniProtKB:P01270 label: Parathyroid hormone function: preferred_term: hormone activity term: id: GO:0005179 label: hormone activity targets: - preferred_term: PTH1R term: id: UniProtKB:Q03431 label: Parathyroid hormone/parathyroid hormone-related peptide receptor locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Calcium-regulating peptide hormone; the signal, not a catalytic participant. PTHLH (PTHrP) is the second PTH1R agonist and is outside this module. gocam_associations: - model: gomodel:67c10cc400004508 activity: gomodel:67c10cc400004508/67c10cc400004538 title: PTH1R-mediated signaling via G-alpha-s following activation by parathyroid hormone (PTH) (Human). description: Same gene and molecular function (GO:0005179). - order: 2 role: PTH1R activation and dual G protein coupling node: id: pth_receptor label: PTH1R couples to Gs and to Gq/11 module_type: REGULATORY_STEP description: >- Agonist-occupied PTH1R acts as a guanine nucleotide exchange factor for Gs, the dominant route, and for Gq/11; a single receptor supports both. annotons: - id: pth1r_receptor label: PTH1R parathyroid hormone receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTH1R term: id: UniProtKB:Q03431 label: Parathyroid hormone/parathyroid hormone-related peptide receptor function: preferred_term: parathyroid hormone receptor activity term: id: GO:0004991 label: parathyroid hormone 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 - preferred_term: phospholipase C-activating G protein-coupled receptor signaling pathway term: id: GO:0007200 label: phospholipase C-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 PTH and PTHrP in kidney and bone; the hub of the module and the target of the scaffold and the GRK/arrestin step. evidence: - source_id: PMID:1313566 statement: >- A single cloned PTH/PTHrP receptor mediates stimulation of both adenylate cyclase and phospholipase C. supporting_text: >- a single cDNA clone, expressing either rat bone or opossum kidney PTH/PTHrP receptor, mediates PTH and PTHrP stimulation of both adenylate cyclase and phospholipase C - source_id: PMID:21777186 statement: PTH1R couples to several G protein subclasses including Gs and Gq/11. supporting_text: >- the PTH1R couples to several G protein subclasses, including Gs, Gq/11, Gi/o and G12/13 gocam_associations: - model: gomodel:67c10cc400004508 activity: gomodel:67c10cc400004508/67c10cc400004509 title: PTH1R-mediated signaling via G-alpha-s following activation by parathyroid hormone (PTH) (Human). description: >- Same gene and the Gs process (GO:0007189); the model types the receptor with the parent GO:0004930 rather than GO:0004991. variant_sets: - id: pth1r_g_protein_routes label: PTH1R G protein routes axis: G protein class selection: ONE_OR_MORE notes: >- The Gs route is the main one; the Gq/11 route is favoured where NHERF scaffolds are expressed. Either or both can carry the signal in a given cell. variants: - id: pth_gs_route label: Gs route (adenylyl cyclase and cAMP) module_type: REGULATORY_STEP description: PTH1R activates G alpha s, which stimulates adenylyl cyclase. annotons: - id: pth_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; added to RGD's gene list because the Gs step cannot be modelled without it. gocam_associations: - model: gomodel:67c10cc400004508 activity: gomodel:67c10cc400004508/67c10cc400004511 title: PTH1R-mediated signaling via G-alpha-s following activation by parathyroid hormone (PTH) (Human). description: Same gene and molecular function (GO:0003925), between PTH1R and ADCY6. - id: pth_gq_route label: Gq/11 route (phospholipase C beta) description: >- Included by reference to the PLC beta step of the generic Gq-PLC-calcium-PKC module; the downstream IP3/calcium and DAG/PKC steps are in that module. module_ref: gpcr_plc_calcium_pkc_signaling#plc_beta_activation - order: 3 role: adenylyl cyclase produces cAMP node: id: pth_adenylyl_cyclase label: Adenylyl cyclase produces cAMP description: >- Included by reference to the adenylyl cyclase step of the generic Gs-cAMP-PKA module; RGD names no cyclase isoform (the PTH1R GO-CAM uses ADCY6). module_ref: gpcr_camp_pka_signaling#adenylyl_cyclase_activation - order: 4 role: PKA activation and output node: id: pth_pka label: PKA activation and substrate phosphorylation description: >- Included by reference to the PKA/CREB step of the generic Gs-cAMP-PKA module. The renal phosphate-transport and bone outputs of PKA are outside this module. module_ref: gpcr_camp_pka_signaling#pka_creb_output - order: 5 role: NHERF/ezrin scaffold biasing of receptor coupling (regulation) optional: true node: id: pth_nherf_ezrin_scaffold label: NHERF1/NHERF2 and ezrin scaffold at the PTH1R carboxy terminus module_type: REGULATORY_STEP description: >- PDZ scaffolds bound to the PTH1R carboxy-terminal motif, linked to actin through ezrin. The complex biases the receptor toward phospholipase C signalling and away from adenylyl cyclase, and in renal proximal tubule it holds the receptor apically. annotons: - id: nherf_scaffold label: NHERF1/NHERF2 PDZ scaffolding of PTH1R and PLC beta participant: selector_type: FAMILY family: preferred_term: NHERF PDZ scaffolds (NHERF1, NHERF2) representative_members: - preferred_term: NHERF1 (EBP50, SLC9A3R1) term: id: UniProtKB:O14745 label: Na(+)/H(+) exchange regulatory cofactor NHE-RF1 - preferred_term: NHERF2 (SLC9A3R2) term: id: UniProtKB:Q15599 label: Na(+)/H(+) exchange regulatory cofactor NHE-RF2 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity targets: - preferred_term: PTH1R carboxy-terminal PDZ-binding motif term: id: UniProtKB:Q03431 label: Parathyroid hormone/parathyroid hormone-related peptide receptor processes: - preferred_term: positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway term: id: GO:1900738 label: positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway - 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 locations: - preferred_term: apical plasma membrane term: id: GO:0016324 label: apical plasma membrane role_description: >- Tether PTH1R and phospholipase C beta 1 side by side, switching the receptor's output from cAMP toward calcium. evidence: - source_id: PMID:12075354 statement: >- NHERF2 binds PLC beta 1 and the PTH1R carboxy-terminal PDZ motif; in cells with the complex, PTH activates PLC beta and inhibits adenylyl cyclase through Gi/o. supporting_text: >- PTH treatment of cells that express the NHERF2 PTH1R complex markedly activates phospholipase C beta and inhibits adenylyl cyclase through stimulation of inhibitory G proteins (G(i/o) proteins). - source_id: PMID:20843475 statement: >- NHERF1/EBP50 confers PTH-stimulated calcium signalling on cells that otherwise respond only with cAMP. supporting_text: >- In contrast, PTHrP(1-36) induced both cAMP and calcium signaling in A10 cells over-expressing EBP50. - id: ezrin_anchor label: Ezrin FERM-domain anchoring of PTH1R and NHERF1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: EZR (ezrin) term: id: UniProtKB:P15311 label: Ezrin function: preferred_term: protein domain specific binding term: id: GO:0019904 label: protein domain specific binding targets: - preferred_term: PTH1R carboxy-terminal tail term: id: UniProtKB:Q03431 label: Parathyroid hormone/parathyroid hormone-related peptide receptor - preferred_term: NHERF1 term: id: UniProtKB:O14745 label: Na(+)/H(+) exchange regulatory cofactor NHE-RF1 locations: - preferred_term: apical plasma membrane term: id: GO:0016324 label: apical plasma membrane role_description: >- Actin-membrane linker binding the PTH1R FERM site and NHERF1; supports apical receptor localization and signalling. It is also an A-kinase anchoring protein for PKA, a role outside this module. evidence: - source_id: PMID:19608645 statement: >- Ezrin binds the PTH1R carboxy-terminal tail directly, and dominant-negative ezrin selectively disrupts apical PTH1R expression and signalling. supporting_text: >- Expression of a dominant-negative ezrin selectively disrupts apical expression and signaling of the PTH1R. - order: 6 role: receptor desensitization (termination) node: id: pth_termination label: GRK2 phosphorylation and beta-arrestin desensitization of PTH1R module_type: REGULATORY_STEP description: >- GRK2 phosphorylates serines in the PTH1R cytoplasmic tail of the agonist-occupied receptor; beta-arrestins bind it, block G protein coupling and drive dynamin-dependent endocytosis. Phosphorylation is required for the uncoupling step, not for internalization, which also has an arrestin-independent route. annotons: - id: pth_grk2 label: GRK2 phosphorylation of PTH1R 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 targets: - preferred_term: PTH1R term: id: UniProtKB:Q03431 label: Parathyroid hormone/parathyroid hormone-related peptide 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: >- The GRK that acts on PTH1R; GRK3 overexpression does not enhance PTH1R phosphorylation, so it is not modelled here. evidence: - source_id: PMID:9849959 statement: >- GRK2, but not GRK3, enhances PTH-stimulated phosphorylation of the PTH receptor, on the same residues used by the endogenous kinase. supporting_text: >- Overexpression of GRK2, but not GRK3, enhanced PTH-stimulated receptor phosphorylation 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 PTH1R. - id: pth_arrestin label: Beta-arrestin uncoupling and endocytosis of PTH1R 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: PTH1R term: id: UniProtKB:Q03431 label: Parathyroid hormone/parathyroid hormone-related peptide 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 the phosphorylated receptor, sterically block G protein coupling and route it into dynamin-dependent endocytosis; RGD associates both arrestins with Pth1r. evidence: - source_id: PMID:12920119 statement: >- PTH1R undergoes beta-arrestin/dynamin-mediated endocytosis in response to the biologically active forms of PTH. supporting_text: >- The PTH1R undergoes beta-arrestin/dynamin-mediated endocytosis in response to the biologically active forms of PTH, PTH-(1-34), and PTH-(1-84). 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: pth_ligand target: pth_receptor connection_type: POSITIVELY_REGULATES description: PTH binding activates PTH1R. - source: pth_gs_route target: pth_adenylyl_cyclase connection_type: POSITIVELY_REGULATES description: G alpha s-GTP stimulates adenylyl cyclase. - source: pth_adenylyl_cyclase target: pth_pka connection_type: PROVIDES_INPUT_FOR description: cAMP activates PKA. - source: pth_nherf_ezrin_scaffold target: pth_gq_route connection_type: POSITIVELY_REGULATES description: >- The NHERF/ezrin complex holds phospholipase C beta 1 at the receptor, favouring the Gq/PLC route. - source: pth_nherf_ezrin_scaffold target: pth_gs_route connection_type: NEGATIVELY_REGULATES description: >- In cells with the NHERF2-PTH1R complex, PTH inhibits adenylyl cyclase through Gi/o instead of stimulating it; NHERF1 either inhibits or leaves the Gs route unchanged (PW:0001135 record text). - source: pth_nherf_ezrin_scaffold target: pth_termination connection_type: NEGATIVELY_REGULATES description: >- NHERF1 also gates receptor endocytosis: it blocks the arrestin-independent internalization that inactive PTH fragments otherwise cause (PMID:12920119). - source: pth_termination target: pth_receptor connection_type: NEGATIVELY_REGULATES description: >- GRK2 phosphorylation and beta-arrestin binding uncouple PTH1R from its G proteins and internalize it.