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

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.

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.