Affinage

PTH1R

Parathyroid hormone/parathyroid hormone-related peptide receptor · UniProt Q03431

Length
593 aa
Mass
66.4 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTH1R is a class B G protein-coupled receptor that transduces parathyroid hormone (PTH) and PTH-related peptide (PTHrP) signals to control skeletal and chondrocyte biology, coupling to multiple effectors including Gs (cAMP), Gq, Gi3, and beta-arrestin pathways (PMID:35914163, PMID:10497171). Agonist binding induces a two-step class B activation involving conformational rearrangement of the extracellular-facing TM5 and TM6 segments and the extracellular domain, whereas antagonist binding leaves the receptor in its basal state (PMID:31670461, PMID:19063682); cryo-EM structures of PTH- and ABL-bound Gs complexes link ligand-specific receptor dynamics to differing signaling duration, and Gq-bound structures define intracellular loop 2 and Galpha C-terminus contacts that govern Gs-versus-Gq coupling selectivity (PMID:36271004, PMID:40571720). Downstream signaling is functionally divisible: cAMP/PKA signaling drives osteogenic responses and gene-expression programs, while beta-arrestin2-dependent signaling preferentially promotes anabolic trabecular bone formation independent of G protein activation (PMID:20368153, PMID:27623777). Receptor output is tuned at multiple levels — by C-terminal tail phosphorylation at Ser/Thr clusters (notably Ser503/Thr504) that selectively governs arrestin3 recruitment and internalization without affecting G-protein coupling (PMID:27623777, PMID:19892016), by the allosteric modulator RAMP2 which preactivates the receptor and biases Gi3 and beta-arrestin2 signaling (PMID:35914163), by extracellular-domain proteolysis by MMP14 that dampens signaling intensity in osteoblasts (PMID:36892459), and by interaction with intracellular partners Kindlin-2 and Gsalpha that facilitate cAMP/CREB output (PMID:33361757). PTH1R also undergoes importin-alpha/beta- and CRM1-dependent nuclear-cytoplasmic shuttling via a bipartite NLS (PMID:17317770, PMID:17627912). Functionally, PTH1R is essential for chondrocyte differentiation, growth-plate and digit formation, and tooth eruption (PMID:32585127, PMID:26620087), and acts as an osteocyte mechanosensor coupling fluid flow to Ca2+ signaling and osteoclast communication (PMID:25529820, PMID:35933642). Loss-of-function and gain-of-function mutations in PTH1R underlie primary failure of tooth eruption, Eiken syndrome, and pseudohypoparathyroidism, generally through impaired cAMP/Galphas signaling, intracellular retention, or altered glycosylation and ligand binding (PMID:27898723, PMID:31986066, PMID:37268817, PMID:35720667).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 High

    Established that PTH1R binds PTH and PTHrP with high affinity and dually activates cAMP and inositol phosphate second messengers, defining its core ligand and effector repertoire relative to a PTHrP-selective paralog.

    Evidence Heterologous expression in COS-7 cells with radioligand binding and cAMP/IP assays (zebrafish receptors)

    PMID:10497171

    Open questions at the time
    • Done in zebrafish receptors and heterologous cells
    • Does not address G-protein subtype identity or arrestin coupling
    • No structural basis for ligand selectivity
  2. 2006 Medium

    Showed PTH1R is not solely a surface receptor but shuttles to the nucleoplasm in complex with importins, opening the question of non-canonical receptor trafficking.

    Evidence Co-IP and PTH-affinity chromatography plus deconvolution microscopy in osteoblast-like cells

    PMID:16574786

    Open questions at the time
    • Functional consequence of nuclear PTH1R undefined
    • Single lab
    • No mapped import signal
  3. 2007 Medium

    Defined the molecular machinery and signal directing PTH1R nuclear-cytoplasmic shuttling, identifying a functional bipartite NLS and bidirectional import/export pathways.

    Evidence Importin-beta siRNA, CRM1 Co-IP, leptomycin B, GFP-NLS fusion targeting assays

    PMID:17317770 PMID:17627912

    Open questions at the time
    • Physiological role of nuclear pool unresolved
    • Cell-cycle linkage correlative
    • No in vivo validation
  4. 2009 High

    Resolved how agonist versus antagonist binding is structurally distinguished and demonstrated that beta-arrestin2 signaling can be uncoupled from G protein signaling to drive anabolic bone formation, establishing biased agonism as physiologically relevant.

    Evidence Engineered disulfide cross-linking of TM5/TM6; biased agonist pharmacology in beta-arrestin2 knockout mice

    PMID:19063682 PMID:20368153

    Open questions at the time
    • Mechanism linking arrestin to bone formation not molecular
    • Structural detail of activation not yet atomic
    • Receptor conformations inferred, not visualized
  5. 2010 Medium

    Dissected the role of C-terminal phosphorylation, showing it controls internalization and cAMP duration but is dispensable for PTH anabolic bone action.

    Evidence Phosphorylation-deficient knock-in mice with micro-CT, in vitro signaling and MKP-1 kinase assays

    PMID:19892016 PMID:20929987

    Open questions at the time
    • Specific phospho-residues not yet mapped
    • Single lab
    • Arrestin recruitment determinants not defined
  6. 2016 High

    Mapped the precise phosphorylation sites governing arrestin3 recruitment and identified a non-peptide agonist binding determinant, linking specific residues to biased signaling and druggability.

    Evidence MS phospho-mapping with mutagenesis and BRET/FRET arrestin assays; PTHR1/PTHR2 chimeras with PCO371

    PMID:27623777 PMID:27857062

    Open questions at the time
    • Phosphatases and kinases acting on tail not identified
    • PCO371 structural pose not resolved at this stage
    • Selectivity over PTHR2 mechanistically inferred
  7. 2019 High

    Provided the first high-resolution structural view of PTH1R activation and showed that ECD engagement can selectively bias pathway coupling.

    Evidence X-ray crystallography of agonist complex; ECD-targeting antibody with HDX-MS and signaling assays

    PMID:31594997 PMID:31670461

    Open questions at the time
    • Crystal required receptor engineering
    • G-protein-bound full-length conformation not captured
    • How ECD antibody blocks arrestin without affecting Gs mechanistically open
  8. 2020 High

    Identified intracellular and patient-relevant determinants of PTH1R signaling: Kindlin-2 as a cytoplasmic facilitator of cAMP/CREB output, and PFE-causing ECD mutations impairing glycosylation and ligand binding.

    Evidence Co-IP and double-haploinsufficiency genetics for Kindlin-2; lentiviral expression and patient iPSC osteoblasts for P119L/P132L

    PMID:31986066 PMID:33361757

    Open questions at the time
    • Structural basis of Kindlin-2 binding undefined
    • Whether Kindlin-2 modulates arrestin arm untested
    • Genotype-phenotype range of PFE mutations incomplete
  9. 2022 High

    Defined ligand-specific signaling duration and allosteric regulation structurally and pharmacologically, with cryo-EM of PTH/ABL-Gs complexes and discovery of RAMP2 as a preactivating allosteric modulator.

    Evidence Cryo-EM with 3D variability analysis and mutagenesis; optical biosensors with RAMP2 plus homology modeling

    PMID:35914163 PMID:36271004

    Open questions at the time
    • In vivo importance of RAMP2 bias incompletely defined
    • Ca2+ allosteric pathway shown only computationally [#36]
    • Link between dynamics and arrestin recruitment not structural
  10. 2023 High

    Demonstrated proteolytic control of receptor abundance and pathogenic mutation mechanisms, including MMP14 ectodomain cleavage and distinct signaling defects in Eiken-syndrome mutants.

    Evidence HC-lineage Mmp14 conditional knockout with cleavage assays; cell-based cAMP and arrestin assays for R485X/E35K/Y134S

    PMID:36892459 PMID:37268817

    Open questions at the time
    • Structural site of MMP14 cleavage not mapped
    • How basal cAMP elevation by R485X arises mechanistically open
    • PTHrP-specific binding loss not structurally resolved
  11. 2025 High

    Resolved the structural basis of Gq coupling selectivity and added a pathogenic Galphas-binding mutation, refining how PTH1R chooses among effectors.

    Evidence Cryo-EM of PTH1R-Gq in two conformations with Gs comparison; WES plus cAMP/RNA-seq/rescue for E302K

    PMID:39988614 PMID:40571720

    Open questions at the time
    • Cellular contexts dictating Gs-versus-Gq use in vivo unclear
    • E302K Galphas affinity loss computational
    • Beta-arrestin-bound full-length structure still absent

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PTH1R integrates its multiple regulatory layers — phosphorylation, RAMP2/Ca2+ allostery, proteolysis, nuclear shuttling, and Kindlin-2 — into context-specific signaling outputs in distinct tissues remains unresolved.
  • No unified model linking arrestin-biased anabolism to specific tail phospho-states in vivo
  • Functional role of nuclear PTH1R pool unknown
  • Tissue-specific effector choice (bone vs. testis vs. skin) not mechanistically reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0140299 molecular sensor activity 2 GO:0048018 receptor ligand activity 1
Localization
GO:0005654 nucleoplasm 3 GO:0005886 plasma membrane 2 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2
Partners
ARRB2FERMT2GNASIPO5LRP6MMP14RAMP2XPO1

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 A beta-arrestin-biased agonist (PTH-betaarr) activates PTH1R through beta-arrestin2 but not G protein signaling, and this beta-arrestin2-dependent pathway preferentially promotes trabecular bone formation without stimulating bone resorption in vivo; ablation of beta-arrestin2 eliminates the anabolic effect of PTH-betaarr and attenuates that of PTH(1-34). Biased agonist pharmacology in mice; beta-arrestin2 knockout mice; bone mineral density measurement Science translational medicine High 20368153
2019 An antibody targeting the alpha-1 helix of the PTH1R extracellular domain (ECD) inhibits beta-arrestin-2 recruitment after PTH(1-34)-driven receptor activation without affecting PTH(1-34)-mediated Gs activation, demonstrating that ECD engagement can selectively modulate downstream signaling pathway coupling. Phage display antibody generation; hydrogen-deuterium exchange mass spectrometry epitope mapping; beta-arrestin-2 recruitment assay; Gs activation assay Scientific reports High 31594997
2016 Mass spectrometry identified nine phosphorylation sites in the C-terminal tail of PTH1R; two clusters (Ser489-Ser495 and Ser501-Thr506) are responsible for the majority of PTH(1-34)-induced phosphorylation; Ser503 and Thr504 in the second cluster account for ~70% of arrestin3 recruitment and are key determinants for arrestin3 interaction, but mutation of these sites does not impair G-protein coupling or ERK1/2 activation. Mass spectrometry phosphorylation mapping; site-directed mutagenesis; FRET and BRET arrestin3 recruitment assays; ERK1/2 activation assay The Biochemical journal High 27623777
2022 Cryo-EM structures of PTH- and ABL-bound PTH1R-Gs complexes revealed similar overall conformations but notable differences in ECD regions and peptide C-terminal portions; 3D variability analysis and mutagenesis showed PTH-bound complexes are less dynamic and more tolerant of mutations than ABL-bound complexes, explaining the longer signaling duration of PTH versus ABL. Cryo-electron microscopy; 3D variability analysis; site-directed mutagenesis; downstream signaling assays Nature communications High 36271004
2019 Crystal structure of PTH1R-agonist complex was determined, revealing the two-step activation mechanism of class B GPCRs and the precise molecular rearrangements during receptor activation. X-ray crystallography; receptor engineering The FEBS journal High 31670461
2025 Cryo-EM structures of PTH1R-Gq complex in two distinct extracellular conformations were determined; N-linked glycans at N176 (N1761.28) stabilize the ligand-tilted conformation; comparison with Gs-bound PTH1R revealed that interactions involving the C-terminus of Gα and the receptor's intracellular loop 2 are critical for Gq signaling selectivity. Cryo-electron microscopy; structural comparison with Gs-bound complex Nature chemical biology High 40571720
2009 Agonist binding (PTH(1-34)) to PTH1R induces conformational changes at the extracellular-facing regions of TM5 and TM6 (detected by engineered disulfide bond formation), whereas the antagonist PTH(7-34) produces no detectable conformational change from the basal inactive state. Engineered disulfide bond formation strategy; cysteine mutagenesis of TM5/TM6 interface; cell membrane preparations Journal of bone and mineral research High 19063682
2022 RAMP2 acts as a specific allosteric modulator of PTH1R, shifting PTH1R to a preactivated state that permits faster ligand-induced activation; RAMP2 modulates downstream signaling in an agonist-dependent manner, specifically increasing PTH-mediated Gi3 signaling sensitivity and increasing both PTH- and PTHrP-triggered beta-arrestin2 recruitment. Optical biosensors measuring PTH1R activation and downstream signaling; homology modeling Proceedings of the National Academy of Sciences of the United States of America High 35914163
2006 PTH1R forms a complex with importin alpha1 and importin beta in osteoblast-like cells, as demonstrated by co-immunoprecipitation and affinity chromatography; nuclear PTH1R is restricted to the nucleoplasm and its nuclear accumulation is associated with specific stages of the cell cycle. Immunofluorescence/deconvolution microscopy; co-immunoprecipitation; PTH-linked affinity chromatography; Western blotting Endocrinology Medium 16574786
2007 PTH1R nuclear-cytoplasmic shuttling is regulated by importin-alpha/beta (for nuclear import) and CRM1/exportin-1 (for nuclear export): importin-beta knockdown decreased nuclear PTH1R; PTH1R and CRM1 co-immunoprecipitated; leptomycin B (CRM1 inhibitor) caused nuclear accumulation of PTH1R. PTHrP treatment induced cytoplasmic localization whereas serum starvation favored nuclear localization. siRNA knockdown of importin-beta; immunofluorescence microscopy; co-immunoprecipitation; leptomycin B treatment; nuclear fractionation Endocrinology High 17317770
2007 The PTH1R contains a functional bipartite nuclear localization signal (NLS) at residues 471-488; GFP fused to this NLS shows significantly increased nuclear targeting compared to GFP alone, confirming the NLS is sufficient for nuclear targeting. GFP fusion protein constructs; transient transfection; fluorescence microscopy; cAMP assay Bone Medium 17627912
2023 MMP14 cleaves the extracellular domain of PTH1R in hypertrophic chondrocyte (HC)-descended osteoblasts, dampening PTH signaling; HC lineage-specific Mmp14 knockout mice produce more bone with enhanced PTH signaling, demonstrating MMP14-mediated proteolytic regulation of PTH1R signaling intensity. Single-cell transcriptomics; conditional knockout mice (HC lineage-specific Mmp14 null); in vitro cleavage assay; PTH1R signaling assays; histomorphometry eLife High 36892459
2020 Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R (via aa 474-475) and with Gsα; Kindlin-2 loss suppresses PTH-induced cAMP production and CREB phosphorylation in osteoblasts; haploinsufficiency of both Kindlin-2 and Pth1r (but not either alone) significantly decreases bone mass, placing both genes in the same pathway; PTH promotes Kindlin-2 expression, creating a positive feedback loop. Co-immunoprecipitation; genetic epistasis (double haploinsufficiency); conditional knockout; cAMP and CREB phosphorylation assays; single-cell RNA profiling Signal transduction and targeted therapy High 33361757
2016 N-cadherin reduces LRP6-PTH1R interaction and endocytosis in response to PTH, blunting PTH suppressive effects on sclerostin/SOST expression and MEF2A/C/D downregulation; in vivo, N-cadherin deletion in osteocytes (Dmp1-cre) accentuated iPTH-induced suppression of sclerostin and bone anabolic effects. In vitro overexpression; immunoblot; qPCR; co-immunoprecipitation (LRP6-PTHR1); conditional knockout mice (Cdh2ΔDmp1) Annals of the New York Academy of Sciences Medium 27723935
2022 PTH suppresses Zfp467 expression via the cAMP/PKA pathway downstream of PTH1R; PTH1R and ZFP467 form a feedback loop where Zfp467 deletion increases NFκB1 nuclear translocation which binds the Pth1r P2 promoter and increases its transcription; Zfp467-/- cells show enhanced cAMP production and osteogenic response to PTH. Conditional knockout mice; dual fluorescence reporter assays; confocal immunofluorescence; qPCR; PKA inhibitor experiments; siRNA knockdown of Pth1r eLife Medium 37159501
2010 PTH1R phosphorylation-deficient (PD) knock-in mice show impaired receptor internalization and sustained cAMP stimulation in vitro; in differentiated osteoblasts, PTHrP-induced dephosphorylation of pERK1/2 is mediated by MKP-1, which is upregulated by PTHrP via PKA and PKC pathways; MKP-1 overexpression inhibits osteoblast proliferation. Phosphorylation-deficient knock-in mice; immunodepletion assay; in vitro kinase assays; MC3T3-E1 cell overexpression; nude mouse ossicle model Cellular signalling Medium 19892016
2010 Phosphorylation-deficient PTH1R (PD) knock-in mice show impaired receptor internalization and sustained cAMP stimulation; PTH1R phosphorylation is not required for PTH anabolic bone formation as both WT and PD mice respond to PTH with increased bone volume and trabecular thickness. Knock-in mouse model; bone densitometry; micro-CT; PTH treatment in vivo The Journal of endocrinology Medium 20929987
2015 PTH1R acts as a mechanosensor in osteocytic MLO-Y4 cells: mechanical stimuli (hypotonic shock, pulsatile fluid flow) prevent cell death through PTHrP-dependent and PTHrP-independent mechanisms; mechanical stimulation rapidly stimulates Ca2+ transients via PTH1R in a PTHrP antiserum-insensitive but PTH1R siRNA-sensitive manner; PTH1R activation by mechanical stimuli induces beta-catenin stabilization and nuclear ERK translocation. PTH1R siRNA knockdown; PTH1R overexpression in HEK-293 cells; pharmacological inhibitors (verapamil, U73122, Rp-cAMPS); live calcium imaging; beta-catenin/ERK immunofluorescence Journal of bone and mineral research Medium 25529820
2022 Fluid flow mechanical stimulation causes redistribution of PTH1R along the entire primary cilium of MLO-Y4 osteocytes; both primary cilium and PTH1R signaling are necessary for osteocyte-to-osteoclast communication; PTH1R activation controls osteoclast function through modulation of CXCL5 and IL-6 secretion, demonstrated by proteomic analysis and neutralizing antibody experiments. Immunofluorescence (PTH1R cilium redistribution); siRNA knockdown of PTH1R and primary cilia components; conditioned media transfer to osteoclast precursors; proteomics; neutralizing antibodies Journal of cellular physiology Medium 35933642
2021 PTH1R activation in epididymis and testis mediates anti-inflammatory effects through the Gq and beta-arrestin-1 signaling pathways, as demonstrated in Gnaq+/- and Arrb1-/- mouse models where the anti-inflammatory effects of PTH1R agonist abaloparatide were attenuated. Gnaq+/- and Arrb1-/- mouse models; LPS/MuV inflammation models; sperm function assays Proceedings of the National Academy of Sciences of the United States of America Medium 34740971
2016 PCO371, a small-molecule agonist, acts as a full agonist of PTH1R without affecting PTHR2; chimeric receptor analysis identified Proline 415 of PTH1R as critical for PCO371-mediated activation, establishing the transmembrane domain binding site for this non-peptide agonist. PTHR1-PTHR2 chimeric receptors; in vivo pharmacology in rats; receptor binding and activation assays Nature communications Medium 27857062
2016 PFE-associated PTH1R mutants (including Gly452Glu) are functionally inactive in cAMP/PKA signaling; the Gly452Glu mutant has a dominant negative effect on WT PTH1R signaling; Gly452Glu is retained intracellularly rather than trafficked to the cell surface; coupling of mutated PTH1R to TRESK K+ channels is completely abolished. HEK293 cell transfection; cAMP ELISA; VASP phosphorylation Western blot; confocal imaging; electrophysiology (Xenopus oocytes) PloS one High 27898723
2020 PFE-associated PTH1R variants P119L and P132L severely reduce N-linked glycosylation and markedly decrease PTH(1-34) binding affinity, leading to severely impaired cAMP accumulation; iPSC-derived osteoblastic cells from a PFE patient with heterozygous P132L mutation show no induction of RANKL by PTH(1-34), consistent with loss of PTH-dependent osteoblast response. Lentiviral expression in HeLa cells; glycosylation assay; PTH binding affinity; cAMP accumulation assay; iPSC differentiation; RANKL expression Journal of dental research High 31986066
2023 Eiken syndrome mutation R485X (truncating the C-terminal tail) increases the basal rate of cAMP signaling and decreases beta-arrestin2 recruitment upon ligand stimulation; ECD mutations E35K and Y134S weaken PTHrP (but not PTH) binding, leading to impaired beta-arrestin2 recruitment and impaired desensitization of cAMP signaling to PTHrP. Cell-based cAMP assays; beta-arrestin2 recruitment assays; ligand binding assays; multiple PTH/PTHrP analogs Communications biology High 37268817
2025 A PFE-associated missense mutation E302K decreases the binding affinity of PTH1R for Gαs (by computational analysis), impairs PTH(1-34)-induced cAMP accumulation, and downregulates the PI3K-AKT signaling pathway; forskolin partially restores osteogenic defects, confirming the cAMP-PI3K/AKT axis as the pathogenic mechanism. Whole exome sequencing; lentiviral stable expression in MG63 cells; cAMP accumulation assay; RNA sequencing; computational binding affinity analysis; rescue experiment with forskolin Progress in orthodontics Medium 39988614
2022 PTH1R mutations R186H and V204E associated with pseudohypoparathyroidism and skeletal defects, respectively, have distinct functional defects: R186H reduces response-maxima without affecting potency and selectively impairs PTH(1-11) analog potency; V204E reduces cell surface expression (Bmax ~44% of WT) and response maxima; both mutants show reduced binding of a short PTH(1-15) radioligand, suggesting impaired interaction with the transmembrane domain binding region. Transient transfection in HEK293 cells; cAMP dose-response assays; antibody binding to HA-tagged receptor; radioligand binding with PTH(1-15) analog; multiple PTH/PTHrP ligand analogs JBMR plus Medium 35720667
2023 PTH1R activation by PTH or PTHrP in osteoblasts mobilizes monocytic MDSCs via VEGF-A and IL-6 expression, which activates Src family kinases in M-MDSCs; Src activation upregulates ADAM-17 and MMP7 in M-MDSCs, leading to VCAM-1 shedding and disruption of M-MDSC tethering to osteoblasts; alpha4beta1 integrin (M-MDSCs) and VCAM-1 (osteoblasts) mediate the initial tethering. In vitro cell-binding assays; Src inhibitor experiments; PTH1R activation; VCAM-1 shedding measurement; VEGF-A/IL-6 expression analysis Bone research Medium 37085481
2023 PTH1R activation in keratinocytes promotes wound re-epithelialization by inducing keratinocyte migration and epithelial-mesenchymal transition (EMT) through the PI3K/AKT signaling pathway; siRNA interference of PTH1R blocked PI3K/AKT activation, confirming PTH1R as upstream of this pathway. siRNA knockdown of PTH1R; PI3K/AKT phosphorylation assays; wound scratch and Transwell migration assays; in vivo wound models Cell communication and signaling Medium 37612710
2014 PTH1R knockdown in osteosarcoma cells markedly reduces invasion through collagen and RANKL expression in vitro; in vivo, PTHR1 knockdown causes profound tumor growth inhibition, increased differentiation/mineralization, upregulation of late osteoblast differentiation genes, Wnt antagonist upregulation, and loss of PRC2-associated gene signatures; Ezh2 inhibition partially recapitulates the differentiation effects. shRNA knockdown; collagen invasion assay; in vivo murine OS model; Ezh2 inhibitor treatment; gene expression analysis Oncogene Medium 25043296
1999 Zebrafish PTH1R (zPTH1R) binds PTH, PTHrP, and fuguPTHrP with high affinity (IC50: 1.2-3.5 nM) and efficiently activates cAMP and inositol phosphate accumulation; a novel receptor zPTH3R shows preferential high-affinity binding for PTHrP over PTH (IC50: 2.1-11.1 nM vs 118-127 nM) and efficient cAMP stimulation by PTHrP but not PTH; zPTH3R does not stimulate inositol phosphate accumulation. COS-7 cell expression; radioligand competition binding; cAMP accumulation assay; inositol phosphate assay The Journal of biological chemistry High 10497171
2017 IL-17 upregulates N-cadherin, which disrupts PTHR1/LRP-6 interaction, thereby inhibiting Wnt signaling and promoting bone loss; combination of PTH and anti-IL17 antibody restores PTHR1/LRP-6 interaction and has synergistic effects on bone parameters. Immunofluorescence of PTHR1 in bone sections; in vivo ovariectomy model; combination treatment Bone Low 28935557
2020 Conditional deletion of PTH1R in Prx1+ mesenchymal progenitors causes arrested mandibular incisor eruption and delayed molar eruption with reduced alveolar bone formation, but does not affect bone resorption; PTH1R-deficient osteofacial bone marrow MSCs show inhibited osteogenic differentiation in vitro; loss of PTH1R also results in aberrant periodontal ligament differentiation with reduced Periostin expression. Conditional knockout (Prx1Cre;PTH1R mice); micro-CT; histomorphometry; in vitro osteogenic differentiation; Cre adenovirus transduction Journal of dental research Medium 32585127
2021 CHD7 regulates osteogenic differentiation of human dental follicle cells by controlling PTH1R transcription; CHD7 knockdown downregulates PTH1R expression and impairs osteogenesis; PTH1R overexpression in CHD7-knockdown cells partially rescues the impaired osteogenic differentiation. RNA-seq; CHD7 knockdown/overexpression; PTH1R overexpression; alkaline phosphatase activity; mineralization assay Stem cells international Medium 33014071
2020 USP7 interacts with Sox9 and Sox9 binds to the PTHrP promoter to promote PTHrP expression; USP7 knockdown inhibits PTHrP/PTH1R signaling; abaloparatide (PTH1R agonist) activates PTH1R to upregulate proliferation and chondrogenic differentiation while downregulating hypertrophic differentiation, confirming the Sox9-PTHrP-PTH1R axis. Co-immunoprecipitation (USP7-Sox9 interaction); chromatin immunoprecipitation (Sox9-PTHrP promoter); siRNA; CCK-8 proliferation; histological staining; in vivo experiments Bone Medium 33127578
2017 Loss of RAMP2 in mice decreases PTH1R (Pthr1) expression in placenta and causes blunted systemic PTH response; RAMP2 loss-of-function thus functionally impacts PTH1R expression and signaling in vivo. Ramp2 knockout mice; PTH administration in vivo; gene expression analysis; placental histology PloS one Medium 28727763
2015 PTH1R conditional deletion in limb mesenchyme (Prx1-Cre;PTH1R(fl/fl) mice) causes symphalangism, demonstrating PTH1R signaling is required for digit formation through chondrocyte differentiation and epiphyseal growth plate formation; Prx1-Cre;Ihh(fl/fl);Jansen Tg rescue mice (constitutively active PTH1R in Ihh mutants) failed to significantly restore digit phenotype, suggesting PTH1R signaling in chondrocytes is insufficient to restore digit formation in the Ihh mutant context. Conditional knockout mice (Prx1-Cre;PTH1R(fl/fl)); Jansen transgene rescue mice; histological analysis; osteocalcin staining Bone Medium 26620087
2022 Molecular dynamics simulations showed that extracellular Ca2+ stabilizes the PTH1R-PTH-Gs protein complex by stabilizing extracellular loop 1 (ECL1) conformation, allosterically promoting the interaction between PTH1R and the Gα5 helix of Gs protein, providing a structural basis for Ca2+ prolonging PTH residence time and receptor activation. Molecular dynamics (MD) and steered MD simulations; MM-GBSA binding energy calculations ACS chemical neuroscience Low 35543321
2021 Phlpp1 deficiency in chondrocytes leads to elevated Pth1r expression (associated with increased H3K27ac at the Pth1r promoter) and enhanced PTH signaling (cAMP, CREB phosphorylation, cell proliferation); PTH(7-34) injection into Phlpp1-/- mice reverses abnormal growth plate and long-bone growth phenotypes, placing Phlpp1 upstream of Pth1r in controlling chondrocyte proliferation. Transcriptomic analysis; H3K27ac ChIP; cAMP assay; CREB phosphorylation; Phlpp1-/- mice; PTH(7-34) in vivo injection Journal of bone and mineral research Medium 33434347

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Science translational medicine 160 20368153
2008 PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption. American journal of human genetics 100 19061984
2021 Physiological and Pharmacological Roles of PTH and PTHrP in Bone Using Their Shared Receptor, PTH1R. Endocrine reviews 87 33564837
1999 Zebrafish express the common parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) and a novel receptor (PTH3R) that is preferentially activated by mammalian and fugufish parathyroid hormone-related peptide. The Journal of biological chemistry 79 10497171
2010 Primary failure of eruption and PTH1R: the importance of a genetic diagnosis for orthodontic treatment planning. American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics 70 20152661
2008 PTHR1 mutations associated with Ollier disease result in receptor loss of function. Human molecular genetics 66 18559376
2004 Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes. Human molecular genetics 62 15525660
2016 Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism. Nature communications 56 27857062
2010 Immunohistochemical identification of the PTHR1 parathyroid hormone receptor in normal and neoplastic human tissues. European journal of endocrinology 52 20156969
2020 Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice. Signal transduction and targeted therapy 50 33361757
2004 Enchondromatosis (Ollier disease, Maffucci syndrome) is not caused by the PTHR1 mutation p.R150C. Human mutation 47 15523647
2019 Inhibition of Ihh Reverses Temporomandibular Joint Osteoarthritis via a PTH1R Signaling Dependent Mechanism. International journal of molecular sciences 45 31382618
2011 Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 45 21404329
2011 The bone-protective effect of genistein in the animal model of bilateral ovariectomy: roles of phytoestrogens and PTH/PTHR1 against post-menopausal osteoporosis. International journal of molecular sciences 45 22312238
2015 Role of the Parathyroid Hormone Type 1 Receptor (PTH1R) as a Mechanosensor in Osteocyte Survival. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 43 25529820
2015 Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism. Seminars in cell & developmental biology 43 26688334
2010 Distinct roles for mitogen-activated protein kinase phosphatase-1 (MKP-1) and ERK-MAPK in PTH1R signaling during osteoblast proliferation and differentiation. Cellular signalling 42 19892016
2013 Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption. Clinical oral investigations 41 23771181
2013 Novel mutations in PTH1R associated with primary failure of eruption and osteoarthritis. Journal of dental research 41 24300310
2014 Knockdown of PTHR1 in osteosarcoma cells decreases invasion and growth and increases tumor differentiation in vivo. Oncogene 40 25043296
2013 Identification of six novel PTH1R mutations in families with a history of primary failure of tooth eruption. PloS one 38 24058597
2020 Role of PTH1R Signaling in Prx1+ Mesenchymal Progenitors during Eruption. Journal of dental research 36 32585127
2020 Long noncoding RNA LINC01278 favors the progression of osteosarcoma via modulating miR-133a-3p/PTHR1 signaling. Journal of cellular physiology 29 31994731
2022 PTH1R Actions on Bone Using the cAMP/Protein Kinase A Pathway. Frontiers in endocrinology 28 35126319
2014 Differential diagnosis of primary failure of eruption (PFE) with and without evidence of pathogenic mutations in the PTHR1 gene. Journal of orofacial orthopedics = Fortschritte der Kieferorthopadie : Organ/official journal Deutsche Gesellschaft fur Kieferorthopadie 28 24825834
2006 Type 1 parathyroid hormone receptor (PTH1R) nuclear trafficking: association of PTH1R with importin alpha1 and beta. Endocrinology 28 16574786
2002 Expression of parathyroid hormone-related peptide (PthrP) and its receptor (PTH1R) during the histogenesis of cartilage and bone in the chicken mandibular process. Journal of anatomy 28 12220122
2022 PTH1R translocation to primary cilia in mechanically-stimulated ostecytes prevents osteoclast formation via regulation of CXCL5 and IL-6 secretion. Journal of cellular physiology 26 35933642
2021 Activation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways. Proceedings of the National Academy of Sciences of the United States of America 26 34740971
2019 Modulation of PTH1R signaling by an ECD binding antibody results in inhibition of β-arrestin 2 coupling. Scientific reports 26 31594997
2018 Parathyroid Hormone-Related Protein Negatively Regulates Tumor Cell Dormancy Genes in a PTHR1/Cyclic AMP-Independent Manner. Frontiers in endocrinology 26 29867773
2018 Hyperstimulation of CaSR in human MSCs by biomimetic apatite inhibits endochondral ossification via temporal down-regulation of PTH1R. Proceedings of the National Academy of Sciences of the United States of America 26 29915064
2016 Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia. The Journal of clinical endocrinology and metabolism 25 27410178
2009 Ischemic injury activates PTHrP and PTH1R expression in human ventricular cardiomyocytes. Basic research in cardiology 25 19190955
2006 A functional polymorphism in the PTHR1 promoter region is associated with adult height and BMD measured at the femoral neck in a large cohort of young caucasian women. Human genetics 25 16508749
2022 Molecular insights into the distinct signaling duration for the peptide-induced PTH1R activation. Nature communications 24 36271004
2010 Decrease in the expression of the type 1 PTH/PTHrP receptor (PTH1R) on chondrocytes in animals with osteoarthritis. Journal of orthopaedic surgery and research 24 20420676
2023 MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism. eLife 22 36892459
2016 Identification of key phosphorylation sites in PTH1R that determine arrestin3 binding and fine-tune receptor signaling. The Biochemical journal 22 27623777
2007 Type 1 parathyroid hormone receptor (PTH1R) nuclear trafficking: regulation of PTH1R nuclear-cytoplasmic shuttling by importin-alpha/beta and chromosomal region maintenance 1/exportin 1. Endocrinology 22 17317770
2007 Genetic variation in the PTH pathway and bone phenotypes in elderly women: evaluation of PTH, PTHLH, PTHR1 and PTHR2 genes. Bone 22 18280230
2022 Functional modulation of PTH1R activation and signaling by RAMP2. Proceedings of the National Academy of Sciences of the United States of America 21 35914163
2021 Validating clinical characteristic of primary failure of eruption (PFE) associated with PTH1R variants. Progress in orthodontics 20 34897565
2017 Combination of PTH (1-34) with anti-IL17 prevents bone loss by inhibiting IL-17/N-cadherin mediated disruption of PTHR1/LRP-6 interaction. Bone 20 28935557
2016 A novel homozygous PTH1R variant identified through whole-exome sequencing further expands the clinical spectrum of primary failure of tooth eruption in a consanguineous Saudi family. Archives of oral biology 20 27019138
2015 Bovine parathyroid hormone enhances osteoclast bone resorption by modulating V-ATPase through PTH1R. International journal of molecular medicine 20 26647715
2021 PTH-rP and PTH-R1 Expression in Placentas from Pregnancies Complicated by Gestational Diabetes: New Insights into the Pathophysiology of Hyperglycemia in Pregnancy. Diagnostics (Basel, Switzerland) 19 34441291
2020 CHD7 Regulates Osteogenic Differentiation of Human Dental Follicle Cells via PTH1R Signaling. Stem cells international 18 33014071
2020 USP7 regulates the proliferation and differentiation of ATDC5 cells through the Sox9-PTHrP-PTH1R axis. Bone 18 33127578
2016 PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling. PloS one 18 27898723
2012 KRT8, FAF1 and PTH1R gene polymorphisms are associated with leg weakness traits in pigs. Molecular biology reports 18 23196707
2007 PTHR1 polymorphisms influence BMD variation through effects on the growing skeleton. Calcified tissue international 18 17885720
2013 Prenatal presentation and postnatal evolution of a patient with Jansen metaphyseal dysplasia with a novel missense mutation in PTH1R. American journal of medical genetics. Part A 17 23950054
2010 Parathyroid hormone-related peptide (PTHrP), parathyroid hormone/parathyroid hormone-related peptide receptor 1 (PTHR1), and MSX1 protein are expressed in central and peripheral giant cell granulomas of the jaws. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 16 20060342
2021 Enzalutamide-induced and PTH1R-mediated TGFBR2 degradation in osteoblasts confers resistance in prostate cancer bone metastases. Cancer letters 15 34752846
2010 Role of PTH1R internalization in osteoblasts and bone mass using a phosphorylation-deficient knock-in mouse model. The Journal of endocrinology 15 20929987
2020 Functional Analysis of PTH1R Variants Found in Primary Failure of Eruption. Journal of dental research 14 31986066
2018 RANKL/OPG system regulation by endogenous PTH and PTH1R/ATF4 axis in bone: Implications for bone accrual and strength in growing rats with mild uremia. Cytokine 14 29529595
2004 The (GT)n polymorphism and haplotype of the COL1A2 gene, but not the (AAAG)n polymorphism of the PTHR1 gene, are associated with bone mineral density in Chinese. Human genetics 14 15599596
2019 PTHR1 May Be Involved in Progression of Osteosarcoma by Regulating miR-124-3p-AR-Tgfb1i1, miR-27a-3p-PPARG-Abca1, and miR-103/590-3p-AXIN2 Axes. DNA and cell biology 13 31536386
2023 Human Parathyroid Hormone Analog (3-34/29-34) promotes wound re-epithelialization through inducing keratinocyte migration and epithelial-mesenchymal transition via PTHR1-PI3K/AKT activation. Cell communication and signaling : CCS 12 37612710
2018 PTH1R-CaSR Cross Talk: New Treatment Options for Breast Cancer Osteolytic Bone Metastases. International journal of endocrinology 12 30151009
2017 A cumulative effect involving malfunction of the PTH1R and ATP4A genes explains a familial gastric neuroendocrine tumor with hypothyroidism and arthritis. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 12 28474257
2016 Pseudohypoparathyroidism type I-b with neurological involvement is associated with a homozygous PTH1R mutation. Genes, brain, and behavior 12 27415614
2016 N-cadherin restrains PTH repressive effects on sclerostin/SOST by regulating LRP6-PTH1R interaction. Annals of the New York Academy of Sciences 12 27723935
2015 Ihh and PTH1R signaling in limb mesenchyme is required for proper segmentation and subsequent formation and growth of digit bones. Bone 12 26620087
2022 Dynamic Balance between PTH1R-Dependent Signal Cascades Determines Its Pro- or Anti-Osteogenic Effects on MSC. Cells 11 36359914
2019 A novel nonsense PTH1R variant shows incomplete penetrance of primary failure of eruption: a case report. BMC oral health 11 31730001
2017 Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation. PloS one 11 28727763
2005 The VDR, COL1A1, PTH, and PTHR1 gene polymorphisms are not associated with bone size and height in Chinese nuclear families. Journal of bone and mineral metabolism 11 16261459
2024 Parathyroid hormone-PTH1R signaling in cardiovascular disease and homeostasis. Trends in endocrinology and metabolism: TEM 10 38429163
2023 Altered Signaling and Desensitization Responses in PTH1R Mutants Associated with Eiken Syndrome. Communications biology 10 37268817
2022 Actions of Parathyroid Hormone Ligand Analogues in Humanized PTH1R Knockin Mice. Endocrinology 10 35460406
2022 Convallatoxin suppresses osteosarcoma cell proliferation, migration, invasion, and enhances osteogenic differentiation by downregulating parathyroid hormone receptor 1 (PTHR1) expression and inactivating Wnt/β-catenin pathway. Bioengineered 10 35635031
2019 Parathyroid hormone-like hormone plays a dual role in neuroblastoma depending on PTH1R expression. Molecular oncology 10 31293052
2017 Transcriptomic analyses reveal the underlying pro-malignant functions of PTHR1 for osteosarcoma via activation of Wnt and angiogenesis pathways. Journal of orthopaedic surgery and research 10 29121993
2011 Type 1 receptor parathyroid hormone (PTH1R) influences breast cancer cell proliferation and apoptosis induced by high levels of glucose. Medical oncology (Northwood, London, England) 10 21312071
2024 Etiological Mechanisms and Genetic/Biological Modulation Related to PTH1R in Primary Failure of Tooth Eruption. Calcified tissue international 9 38833001
2023 Substantially Delayed Maturation of Growth Plate Chondrocytes in "Humanized" PTH1R Mice with the H223R Mutation of Jansen's Disease. JBMR plus 9 37808400
2019 Primary failure of eruption of teeth in two siblings with a novel mutation in the PTH1R gene. European archives of paediatric dentistry : official journal of the European Academy of Paediatric Dentistry 9 30904994
2017 Twenty-year follow-up of a familial case of PTH1R-associated primary failure of tooth eruption. American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics 9 28257744
2009 Association of parathyroid hormone-like hormone (PTHLH) and its receptor (PTHR1) with the number of functional and inverted teats in pigs. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 9 19646152
2003 Expression patterns of parathyroid hormone-related peptide (PTHrP) and parathyroid hormone receptor type 1 (PTHR1) during human development are suggestive of roles specific for each gene that are not mediated through the PTHrP/PTHR1 paracrine signaling pathway. Gene expression patterns : GEP 9 12609604
2023 PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner. eLife 8 37159501
2017 In silico and functional evaluation of PTH1R mutations found in patients with primary failure of eruption (PFE). Orthodontics & craniofacial research 8 28643929
2004 PTH-1R responses to PTHrP and regulation by vitamin D in keratinocytes and adjacent fibroblasts. The Journal of steroid biochemistry and molecular biology 8 15225805
2025 A novel PTH1R mutation causes primary failure of eruption via the cAMP-PI3K/AKT pathway. Progress in orthodontics 7 39988614
2023 Mobilization of monocytic myeloid-derived suppressor cells is regulated by PTH1R activation in bone marrow stromal cells. Bone research 7 37085481
2022 Critical Extracellular Ca2+ Dependence of the Binding between PTH1R and a G-Protein Peptide Revealed by MD Simulations. ACS chemical neuroscience 7 35543321
2021 Pleckstrin homology (PH) domain and Leucine Rich Repeat Phosphatase 1 (Phlpp1) Suppresses Parathyroid Hormone Receptor 1 (Pth1r) Expression and Signaling During Bone Growth. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 7 33434347
2021 PTHR1 in osteosarcoma: Specific molecular mechanisms and comprehensive functional perspective. Journal of cellular and molecular medicine 7 33675132
2020 A 51 bp indel polymorphism within the PTH1R gene is significantly associated with chicken growth and carcass traits. Animal genetics 7 32400914
2012 Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice. American journal of physiology. Endocrinology and metabolism 7 22338074
2009 PTH and PTH antagonist induce different conformational changes in the PTHR1 receptor. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 7 19063682
2008 Quantitative comparison of PTH1R in breast cancer MCF7 and osteosarcoma SaOS-2 cell lines. Cell biochemistry and function 7 18395846
2007 Expression of PTH1R constructs in LLC-PK1 cells: protein nuclear targeting is mediated by the PTH1R NLS. Bone 7 17627912
2005 Parathyroid hormone-related peptide (hPTHrP) and parathyroid hormone-related peptide receptor type 1 (PTHR1) expression in human thymus. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 7 15879577
2025 Insights into G-protein coupling preference from cryo-EM structures of Gq-bound PTH1R. Nature chemical biology 6 40571720
2022 Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism. JBMR plus 6 35720667
2019 New views into class B GPCRs from the crystal structure of PTH1R. The FEBS journal 6 31670461

Missed literature

Know a paper Affinage missed for PTH1R? Flag it for the maintainers and the community.

No submissions yet.