Affinage

GPRC6A

G-protein coupled receptor family C group 6 member A · UniProt Q5T6X5

Length
926 aa
Mass
104.8 kDa
Annotated
2026-04-28
83 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPRC6A is a Family C G-protein-coupled receptor that functions as a multiligand metabolic sensor, coupling primarily through Gαq upon activation by basic L-amino acids (L-arginine, L-lysine, L-ornithine) as orthosteric agonists, with divalent cations (Ca²⁺, Mg²⁺) serving as positive allosteric modulators, and testosterone binding directly within the seven-transmembrane domain (PMID:15576628, PMID:17245368, PMID:26440882). Osteocalcin acts as a positive allosteric modulator at a distinct site in the Venus flytrap domain, while a common human ICL3 KGKY polymorphism causes intracellular retention and shifts signaling to β-arrestin-dependent ERK/AKT/mTORC1 pathways (PMID:39399472, PMID:27986810, PMID:30894404). The receptor forms disulfide-linked homodimers via C131, undergoes constitutive Rab11-dependent recycling internalization, and its surface expression is regulated by N-glycosylation (PMID:25617829, PMID:28280242). Conditional knockout studies across multiple tissues establish GPRC6A as a critical regulator of pancreatic β-cell insulin secretion and proliferation, hepatic glucose and lipid metabolism, adipocyte lipolysis, Leydig cell steroidogenesis, osteoblast mineralization, intestinal GLP-1 secretion, and ILC3-mediated mucosal immunity (PMID:24009262, PMID:32350388, PMID:33428938, PMID:22872579, PMID:23269670, PMID:35134872).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 High

    GPRC6A was deorphanized as a promiscuous basic L-amino acid receptor of the Family C GPCR class, resolving the identity of its primary agonists and establishing its structural relationship to CaSR and mGluRs.

    Evidence Chimeric receptor expression in Xenopus oocytes and tsA cells measuring Ca²⁺-dependent Cl⁻ currents and intracellular calcium; independent cloning from human kidney cDNA library with expression profiling

    PMID:15194188 PMID:15576628

    Open questions at the time
    • Wild-type human receptor could not be functionally expressed at the cell surface
    • Coupling pathway (Gq vs other G proteins) not yet defined
    • Physiological roles unknown
  2. 2007 High

    Quantitative pharmacological characterization established that wild-type mouse GPRC6A couples to Gαq, with basic amino acids as agonists and divalent cations as positive allosteric modulators rather than direct agonists.

    Evidence Inositol phosphate turnover assay with Gαq(G66D) co-expression and Xenopus oocyte assay

    PMID:17245368

    Open questions at the time
    • Whether Gi or Gs pathways are also engaged remained unresolved
    • Human receptor still not functionally expressed
  3. 2008 High

    Global GPRC6A knockout revealed the receptor as a pleiotropic metabolic and endocrine regulator, with KO mice exhibiting osteopenia, feminization, metabolic syndrome, and renal mineral handling defects.

    Evidence Global Gprc6a KO mouse phenotyping across bone, endocrine, metabolic, and renal systems

    PMID:19050760

    Open questions at the time
    • Cell-autonomous vs systemic contributions to each phenotype unresolved
    • Specific ligands driving each tissue phenotype not identified
  4. 2009 High

    Non-competitive antagonists and mutagenesis of the 7TM domain identified an allosteric pocket distinct from the orthosteric amino acid binding site in the VFT, establishing dual-domain pharmacology.

    Evidence Site-directed mutagenesis of 7TM residues (F666A, F670A, W797A, E816Q) with IP assay and 3D homology modeling

    PMID:19836834

    Open questions at the time
    • No crystal or cryo-EM structure available
    • Allosteric mechanism of signal transduction between domains unknown
  5. 2010 High

    GPRC6A was identified as a receptor for non-genomic testosterone signaling and as a mediator of osteoblast mineralization, establishing it as a sensor for both steroid and mineral cues.

    Evidence Testosterone-induced ERK activation in HEK-293 (no AR), attenuated in GPRC6A⁻/⁻ BMSCs and in vivo; KO osteoblasts showed impaired Ca²⁺-stimulated ERK and mineralization

    PMID:19874200 PMID:20947496

    Open questions at the time
    • Whether testosterone binds directly to GPRC6A or acts indirectly was unknown
    • Mechanism linking GPRC6A to mineralization not delineated
  6. 2011 High

    GPRC6A was established as the osteocalcin receptor mediating β-cell insulin secretion and as a promoter of prostate cancer progression, revealing its endocrine and oncogenic roles.

    Evidence Ocn-stimulated ERK/insulin in WT but not Gprc6a⁻/⁻ mice; siRNA KD in prostate cancer cells and GPRC6A⁻/⁻/TRAMP compound mouse model

    PMID:21425331 PMID:21681779

    Open questions at the time
    • Osteocalcin binding site on GPRC6A not mapped
    • Whether osteocalcin is orthosteric or allosteric was unclear
  7. 2012 High

    Cell-type-specific studies demonstrated GPRC6A mediates L-arginine-stimulated insulin secretion in β-cells via ERK and cAMP, and GLP-1 secretion from intestinal L-cells via PLC/IP3, defining it as a nutrient-sensing incretin axis component.

    Evidence Gprc6a⁻/⁻ islet ex vivo secretion assays and siRNA KD in GLUTag L-cells with calcium imaging and GLP-1 measurement

    PMID:22872579 PMID:23269670

    Open questions at the time
    • Relative contribution of amino acid vs osteocalcin sensing in each tissue not resolved
    • Whether cAMP generation is direct Gs coupling or indirect was unclear
  8. 2013 High

    Conditional β-cell Gprc6a deletion proved cell-autonomous regulation of β-cell proliferation via cyclin D1, and rigorous pharmacology confirmed exclusive Gq coupling for amino acid/cation ligands while failing to reproduce testosterone or osteocalcin agonism in stable CHO cells.

    Evidence β-cell-specific KO (Ins2-Cre) with proliferation quantification; stable CHO cell IP1 assay for multiple G-protein pathways

    PMID:24008333 PMID:24009262

    Open questions at the time
    • Discrepancy between CHO and other cell systems regarding testosterone/Ocn agonism unresolved
    • Whether coupling pathway differs between receptor variants not yet addressed
  9. 2015 High

    Direct testosterone binding to the 7TM domain was demonstrated and the receptor was shown to form C131-linked homodimers with N-glycosylation regulating surface expression, providing the first biochemical characterization of GPRC6A post-translational modifications and steroid binding.

    Evidence Direct ligand binding assay with 7TM mutagenesis and KO validation; C131 mutagenesis under reducing/non-reducing Western blot

    PMID:25617829 PMID:26440882

    Open questions at the time
    • High-resolution structure still lacking
    • Whether dimerization is required for function not tested
  10. 2016 High

    The human ICL3-KGKY insertion was identified as the cause of intracellular retention of human GPRC6A, resolving a long-standing discrepancy between mouse and human receptor surface expression; the ancestral RKLP sequence permits normal trafficking.

    Evidence Systematic chimeric human/mouse receptor mutagenesis, bonobo receptor comparison, surface expression and IP assays

    PMID:27986810

    Open questions at the time
    • Whether intracellularly retained KGKY receptor signals from endosomes not yet tested
    • Population-level functional consequences of KGKY vs RKLP not established
  11. 2017 High

    Constitutive Rab11-dependent recycling internalization was established as the dominant trafficking mode, and CRISPR KO confirmed GPRC6A drives prostate cancer growth via ERK/AKT/mTOR in xenograft models.

    Evidence FRET-based internalization assay with Rab marker co-localization; CRISPR KO in PC-3 cells with xenograft

    PMID:28280242 PMID:28659174

    Open questions at the time
    • Whether constitutive internalization serves a signaling function or is merely trafficking unknown
    • Structural basis of KGKY-mediated intracellular retention unresolved
  12. 2019 High

    The intracellularly retained human KGKY variant was shown to signal via β-arrestin-dependent ERK/AKT/mTORC1 rather than canonical Gq, redefining human GPRC6A as a biased receptor capable of intracellular signaling.

    Evidence CRISPR KO in PC-3, overexpression comparison of KGKY vs RKLP variants, β-arrestin assay, mTOR phosphorylation

    PMID:30894404

    Open questions at the time
    • Whether β-arrestin signaling occurs from endosomes specifically not shown
    • Physiological relevance of intracellular signaling in humans not established in vivo
  13. 2020 High

    Conditional hepatocyte-specific GPRC6A deletion established cell-autonomous regulation of hepatic glucose, glycogen, and lipid metabolism, and knock-in of the human KGKY variant revealed gain-of-function metabolic effects in vivo.

    Evidence Liver-specific Gprc6a KO with metabolic phenotyping and transcriptomics; CRISPR knock-in of KGKY in mouse

    PMID:32350388 PMID:32636482

    Open questions at the time
    • Specific hepatic ligand (amino acid vs osteocalcin) driving metabolic effects not identified
    • Mechanism of KGKY gain-of-function in liver not defined
  14. 2021 High

    Adipocyte-specific GPRC6A KO demonstrated cell-autonomous regulation of lipolysis via ATGL/HSL, extending the metabolic sensor role to adipose tissue energy expenditure.

    Evidence Adipocyte-specific KO on HFD with lipolytic enzyme expression; GluOC/ornithine ATGL induction in 3T3-L1 cells

    PMID:33428938

    Open questions at the time
    • Signaling pathway from GPRC6A to ATGL transcription not defined
    • Whether adipocyte GPRC6A contributes to systemic insulin sensitivity not tested
  15. 2022 Medium

    GPRC6A was identified as a mediator of amino acid sensing in ILC3 innate lymphocytes, where L-arginine activates mTORC1 to expand ILC3s and promote IL-22 production for mucosal immunity.

    Evidence GPRC6A KO mouse with DSS colitis and C. rodentium infection, purified ILC3 mTORC1 signaling assay

    PMID:35134872

    Open questions at the time
    • Whether GPRC6A acts cell-autonomously in ILC3s requires conditional KO
    • Interaction with other amino acid sensors (e.g., mTORC1 upstream regulators) not delineated
  16. 2024 Medium

    Osteocalcin was reclassified as a positive allosteric modulator binding a VFT site distinct from the orthosteric amino acid pocket, with alternatively spliced isoforms lacking VFT regions losing osteocalcin responsiveness; in parallel, GPRC6A-dependent testosterone cardiotoxicity was demonstrated in zebrafish via Pak1 signaling.

    Evidence AlphaFold2 modeling with K352E/H355P mutagenesis and isoform functional assays; zebrafish gprc6a mutant and antagonist with RNA-seq

    PMID:39399472 PMID:39479956

    Open questions at the time
    • No experimental structure of the osteocalcin–VFT interface exists
    • Relevance of zebrafish cardiac phenotype to mammalian cardiovascular biology unknown
  17. 2025 Medium

    GPRC6A was shown to function as a kokumi taste receptor in type II taste cells and to promote tau accumulation via mTORC1 in tauopathy models, revealing new sensory and neurodegenerative roles.

    Evidence GPRC6A antagonist in rat two-bottle preference and chorda tympani recordings; overexpression/KD/antagonism in tau cell models

    PMID:40309958 PMID:40848921

    Open questions at the time
    • Whether GPRC6A is required for kokumi taste in genetic KO models not tested
    • In vivo relevance of GPRC6A-mTORC1-tau axis in neurodegeneration not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution experimental structure of GPRC6A (alone or in complex with ligands) remains unavailable, and the structural basis for biased signaling between KGKY and RKLP ICL3 variants, the mechanism of intracellular β-arrestin signaling, and the identity of the endogenous ligand(s) driving each tissue-specific metabolic phenotype are unresolved.
  • No cryo-EM or crystal structure at atomic resolution
  • Structural basis of ICL3 variant-dependent biased signaling unknown
  • Endogenous ligand hierarchy in each tissue not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2
Partners
ARRB1BGLAPRAB11ASHBG

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 GPRC6A was deorphanized as a promiscuous L-alpha-amino acid receptor with preference for basic amino acids (L-Arg, L-Lys, L-ornithine); a chimeric receptor construct (h6A/5.24) using the ATD of hGPRC6A with the transmembrane/C-terminus of goldfish 5.24 was used to achieve surface expression and functional assay; agonist activity was confirmed in Xenopus oocytes (Ca2+-dependent Cl- currents) and tsA cells (intracellular calcium). Chimeric receptor expression, Xenopus oocyte electrophysiology, intracellular calcium assay, homology modeling Molecular pharmacology High 15576628
2004 GPRC6A is a Family C GPCR with a 590-amino acid amino-terminal domain (ATD), seven-transmembrane domain, and high homology to CaSR (34%), T1R1 (28%), and mGluR1 (24%); it is widely expressed with highest levels in kidney, skeletal muscle, testis, and leucocytes; three isoforms exist as naturally occurring splice variants. cDNA cloning from human kidney library, sequence analysis, RT-PCR expression profiling Gene High 15194188
2007 Wild-type mouse GPRC6A couples to Gq signaling; basic L-alpha-amino acids (ornithine, lysine, arginine) are the most potent agonists; divalent cations (Ca2+, Mg2+) do not activate Gq signaling per se but positively modulate the amino-acid response. Assay used co-expression with promiscuous Galpha(qG66D) protein in inositol phosphate turnover assay. Cell-based inositol phosphate turnover assay with Galpha(qG66D) co-expression, Xenopus oocyte assay British journal of pharmacology High 17245368
2008 GPRC6A null mice exhibit osteopenia, feminization (decreased testosterone, increased estradiol), metabolic syndrome (hepatic steatosis, hyperglycemia, glucose intolerance, insulin resistance), abnormal renal calcium/phosphorus handling, and impaired osteoblast mineralization; GPRC6A is highly expressed in Leydig cells and kidney tubules. Global GPRC6A knockout mouse phenotyping (metabolic, bone, renal, endocrine readouts) PloS one High 19050760
2009 Non-competitive antagonists of GPRC6A (calindol, NPS2143) were identified; mutagenesis of transmembrane domain residues F666A(3.32), F670A(3.36), W797A(6.48) abolished L-ornithine activation; E816Q(7.39) selectively lost calindol but not NPS2143 antagonism, mapping an allosteric binding pocket in the 7TM domain. Site-directed mutagenesis, inositol phosphate assay, 3D homology modeling of GPRC6A 7TM Cell calcium High 19836834
2010 GPRC6A mediates non-genomic (rapid, transcription-independent) effects of testosterone and other steroids; overexpression in HEK-293 cells lacking androgen receptor confers testosterone-induced ERK phosphorylation; ERK activation is attenuated in bone marrow stromal cells from GPRC6A-/- mice and in 22Rv1 cells after siRNA-mediated knockdown; GPRC6A-/- mice show impaired testosterone-induced ERK activation and Egr-1 expression in vivo. Overexpression in HEK-293, siRNA knockdown, GPRC6A-/- mouse in vivo testosterone challenge, ERK phosphorylation assay The Journal of biological chemistry High 20947496
2010 GPRC6A directly participates in osteoblast-mediated bone mineralization; osteoblasts and BMSCs from GPRC6A-/- mice show attenuated extracellular calcium-stimulated ERK activation, diminished ALP expression, and impaired mineralization ex vivo; siRNA knockdown in MC3T3 osteoblasts also reduced calcium-stimulated ERK activity. GPRC6A-/- primary osteoblast culture, siRNA knockdown in MC3T3 cells, ERK phosphorylation assay, mineralization assay Journal of bone and mineral research High 19874200
2011 GPRC6A mediates osteocalcin (Ocn) signaling in pancreatic β-cells; transfection of HEK-293 with GPRC6A confers dose-dependent Ocn-stimulated PKD1 and ERK phosphorylation; Ocn stimulates ERK in TC-6 β-cells; intraperitoneal Ocn stimulates pancreatic ERK and serum insulin in wild-type mice but not in Gprc6a-/- mice. Heterologous expression in HEK-293, ERK phosphorylation assay, GPRC6A-/- mouse in vivo Ocn challenge Journal of bone and mineral research High 21425331
2011 GPRC6A promotes prostate cancer cell proliferation, chemotaxis, ERK activation, PSA and Runx2 gene expression in response to calcium, osteocalcin, and arginine; siRNA knockdown of GPRC6A inhibits these responses; Gprc6a deficiency in TRAMP mice retards prostate cancer progression and improves survival. siRNA knockdown in prostate cancer cell lines, GPRC6A-/-/TRAMP compound mouse model, ERK assay, proliferation/chemotaxis assay The Prostate High 21681779
2012 GPRC6A mediates L-arginine-induced GLP-1 secretion from intestinal L cells (GLUTag line); L-ornithine increases [Ca2+]i via GPRC6A-dependent, PLC/IP3-mediated pathway; siRNA depletion of GPRC6A inhibits L-ornithine-induced [Ca2+]i increase and GLP-1 secretion. siRNA knockdown, pharmacological inhibition (GPRC6A antagonist, PLC inhibitor, IP3R antagonist), calcium imaging, GLP-1 secretion assay The Journal of biological chemistry High 23269670
2012 GPRC6A mediates L-arginine-stimulated insulin secretion and ERK/cAMP responses in pancreatic β-cells; islets from Gprc6a-/- mice show decreased size and insulin content, reduced ERK response to L-Arg in vivo, and diminished L-Arg-induced insulin secretion and cAMP accumulation ex vivo. Gprc6a-/- mouse islet isolation, ex vivo insulin secretion, cAMP accumulation assay, ERK phosphorylation Endocrinology High 22872579
2013 GPRC6A couples exclusively to the Gq pathway in response to basic L-amino acids and divalent cations in stably expressing CHO cells; Gi- and Gs-mediated signaling, testosterone and osteocalcin agonism could not be confirmed in this system using HTRF-based IP1 assay. Stable CHO cell line, HTRF-based IP1 Gq assay, Gi/Gs pathway assays The Journal of pharmacology and experimental therapeutics High 24008333
2013 Osteocalcin regulates β-cell proliferation in a cyclin D1-dependent manner through Gprc6a; conditional deletion of Gprc6a in β-cells (Ins2-Cre) causes glucose intolerance due to impaired insulin production and reduced β-cell mass accrual during perinatal and adult periods. Conditional (β-cell-specific) Gprc6a knockout (Gprc6aflox/flox × Ins2-Cre), glucose tolerance test, β-cell mass/proliferation quantification Diabetes High 24009262
2014 GPRC6A mediates L-arginine-stimulated fibroblast proliferation through ERK1/2 and PI3K/Akt signaling; siRNA knockdown of GPRC6A blocked proliferation and decreased phosphorylation of ERK1/2, Akt, PKA, and CREB. siRNA knockdown, in vitro kinase assay, cell proliferation assay PloS one Medium 24651445
2014 Uncarboxylated osteocalcin stimulates CYP2R1 expression and 25-OH Vitamin D production in Leydig cells (MA-10 line) through GPRC6A; this effect was blocked by anti-GPRC6A antibody; ucOC induced phasic intracellular calcium increase (distinct from hCG-induced slow tonic calcium/cAMP response), signaling through ERK1/2 phosphorylation. Anti-GPRC6A antibody blockade, intracellular calcium measurement, ERK phosphorylation, CYP2R1 protein expression, 25-OH Vit D measurement in culture medium Endocrinology Medium 25093461
2014 Testosterone activates GPRC6A in keratinocytes to stimulate Gq/IP3-mediated intracellular calcium mobilization, activating Duox1 and generating H2O2, leading to caspase-3-dependent apoptosis; siRNA knockdown of GPRC6A inhibited testosterone-induced calcium mobilization and H2O2 generation. siRNA knockdown, calcium imaging, H2O2 measurement, caspase-3 assay, 3D skin equivalent model The Journal of biological chemistry Medium 25164816
2015 GPRC6A is a homodimer linked by a disulfide bridge between C131 residues in the extracellular ATD; N-glycosylation at seven sites regulates surface expression and function (one site modulates surface expression, another affects receptor function). Site-directed mutagenesis, Western blot under reducing/non-reducing conditions, surface expression assay FEBS letters High 25617829
2015 Testosterone directly binds to GPRC6A; computational structural models identified binding poses in the transmembrane domain; mutations of predicted binding site residues blocked testosterone activation; Gprc6a-/- mice show loss of testosterone rapid signaling, impaired testosterone-stimulated insulin secretion in islets, and impaired testosterone biosynthesis enzyme expression in Leydig cells. Direct ligand binding assay, computational modeling, mutagenesis of binding site, Gprc6a-/- mouse functional assays Molecular endocrinology High 26440882
2016 Osteocalcin (Ocn) and an Ocn-derived C-terminal hexapeptide directly activate GPRC6A-dependent ERK signaling in vitro; computational docking predicts Ocn hexapeptide binds to the extracellular side of the transmembrane domain; mutations in the predicted binding pocket (confirmed by modeling) reduce Ocn and hexapeptide activation; conditional β-cell Gprc6a deletion reduces islet number, insulin content, β-cell proliferation, and impairs glucose tolerance. In vitro ERK signaling assay, computational docking, site-directed mutagenesis, conditional (β-cell) Gprc6a KO mouse Endocrinology High 27007074
2016 A human KGKY insertion/deletion polymorphism in the third intracellular loop (ICL3) of GPRC6A is responsible for intracellular retention and loss of cell surface expression in most humans; the ancestral RKLP sequence (present in all other species and ~40% of Africans) confers cell surface expression and Gq-coupled function; identified via chimeric human/mouse receptor analysis and bonobo receptor comparison. Chimeric receptor analysis, mutagenesis, surface expression assay, inositol phosphate assay, bonobo GPRC6A cloning The Journal of biological chemistry High 27986810
2016 GPRC6A rs2274911 (P91S) polymorphism and F464Y inactivating mutation are associated with reduced receptor membrane exposition and decreased downstream ERK1/2 phosphorylation in functional studies, linking GPRC6A function to testosterone exposure and testicular function. In vitro functional assay of mutant receptors, ERK1/2 phosphorylation, surface expression analysis The Journal of clinical endocrinology and metabolism Medium 26735260
2016 Sex hormone-binding globulin (SHBG) binds to GPRC6A at the same binding site as osteocalcin (ucOC), as shown by competitive displacement experiments on HEK-293 cells transfected with human GPRC6A; unliganded SHBG suppresses Erk1/2 phosphorylation induced by ucOC; SHBG saturated with testosterone lacks binding/stimulating activity; mutations of the GPRC6A binding site confirm shared binding locus. Competitive binding assay on transfected HEK-293, ERK1/2 phosphorylation assay, GPRC6A mutation constructs, computational docking Endocrinology Medium 27673554
2017 GPRC6A undergoes predominantly constitutive (agonist-independent) internalization; after endocytosis, it co-localizes with Rab5 (early endosomes) and Rab11 (slow recycling endosomes) but not Rab7 (late endosomes), indicating recycling via the slow Rab11-positive pathway. Antibody feeding internalization assay, FRET-based real-time internalization assay, confocal co-localization with Rab protein markers The Journal of biological chemistry High 28280242
2019 Human GPRC6A (ICL3_KGKY variant) is retained intracellularly in ligand-naive cells but signals via β-arrestin-dependent ERK, AKT, and mTORC1 pathways in response to testosterone; CRISPR/Cas9 knockout of GPRC6A in PC-3 cells abolishes testosterone-stimulated ERK, AKT, mTORC1 activation, cell proliferation, and autophagy inhibition; testosterone activation requires extracellular calcium. CRISPR/Cas9 KO, overexpression of mouse/human/humanized GPRC6A in HEK-293, ERK/AKT/mTOR phosphorylation assay, β-arrestin assay, proliferation assay, autophagy assay Molecular pharmacology High 30894404
2020 A newly identified osteocalcin-derived pentadecapeptide (metabolitin/MTL) binds to GPRC6A as shown by ligand-receptor binding assay, receptor internalization, BRET, and nano ITC assays; MTL binding to GPRC6A in intestines inhibits neurotensin secretion, suppressing triglyceride absorption via AMPK pathway, and induces GLP-1 secretion. Ligand-receptor binding assay, receptor internalization assay, BRET, nano isothermal titration calorimetry, in vivo mouse NAFLD model Journal of hepatology Medium 32147363
2020 Conditional hepatocyte-specific deletion of Gprc6a (Alb-Cre × Gprc6aflox/flox) causes hepatic fat accumulation, glycogen depletion, impaired glucose and pyruvate tolerance, decreased circulating FGF-21, and transcriptomic alterations in glucose/fat/glycogen metabolism pathways, demonstrating direct GPRC6A regulation of hepatic energy metabolism. Conditional (liver-specific) Gprc6a KO, metabolic phenotyping, liver transcriptome analysis, glucose/pyruvate tolerance tests Scientific reports High 32350388
2020 The human GPRC6A-KGKY variant (knock-in mice) behaves as a gain-of-function polymorphism in vivo, reducing basal blood glucose and increasing serum insulin and FGF-21, improving glucose tolerance, with altered liver transcriptome in glucose/glycogen/fat metabolism pathways. CRISPR/Cas9 knock-in of human KGKY sequence in mouse Gprc6a, metabolic phenotyping, liver transcriptome analysis Scientific reports Medium 32636482
2021 Adipocyte-specific GPRC6A knockout mice on high-fat/high-sucrose diet develop increased adipose tissue weight, adipocyte hypertrophy, and adipose inflammation with reduced lipolytic activity (downregulation of ATGL and HSL); GluOC and ornithine increase ATGL expression in 3T3-L1 adipocytes in a GPRC6A-dependent manner, indicating GPRC6A mediates lipolysis in adipocytes. Adipocyte-specific Gprc6a KO mouse, high-fat diet challenge, lipolytic enzyme expression, in vitro 3T3-L1 adipocyte assays The Journal of biological chemistry High 33428938
2021 Liver-specific GPRC6A knockout mice (GPRC6ALKO) are not protected from high-fat diet-induced NAFLD by uncarboxylated osteocalcin treatment, while wild-type mice are; GPRC6A mediates osteocalcin effects in liver by inhibiting lipid synthesis and promoting lipolysis through differential mRNA expression of lipogenesis/lipolysis genes. Liver-specific GPRC6A KO, high-fat diet NAFLD model, osteocalcin treatment, differential gene expression analysis International journal of endocrinology Medium 33531899
2022 GPRC6A in colonic ILC3s mediates L-arginine-induced ILC3 expansion and IL-22 production via mTORC1 signaling; GPRC6A-/- mice show decreased ILC3-derived IL-22 and increased susceptibility to colitis; L-arginine (GPRC6A agonist) promotes ILC3 expansion via mTORC1 in vitro and attenuates DSS-induced colitis in vivo. GPRC6A KO mouse, DSS-induced colitis model, C. rodentium infection, purified ILC3 culture, mTORC1 signaling assay, IL-22 measurement Journal of Crohn's & colitis Medium 35134872
2024 Osteocalcin acts as a positive allosteric modulator (PAM) of GPRC6A by binding to a site in the Venus fly trap (VFT) domain that is distinct from the orthosteric site for calcium and L-amino acids; alternatively spliced GPRC6A isoforms 2 and 3 (lacking regions of the VFT) and mutations K352E/H355P in the predicted Ocn binding site prevent Ocn activation. AlphaFold2 structural modeling, mutagenesis (K352E, H355P), functional assay with alternatively spliced isoforms, ERK signaling assay FASEB bioAdvances Medium 39399472
2024 In zebrafish embryos, testosterone causes cardiac edema via GPRC6A independent of nuclear androgen receptor (AR); gprc6a mutants show significantly reduced cardiac edema after testosterone exposure; GPRC6A antagonist co-treatment suppresses cardiac edema; RNA-seq and rescue approaches identified reduced Pak1 signaling as the downstream mechanism. Zebrafish gprc6a mutant, pharmacological antagonism, RNA-seq, RNA rescue, cardiac edema quantification Development High 39479956
2025 GPRC6A acts as a kokumi receptor in rat taste cells; ornithine enhances taste preferences (umami, sweet, fatty, salty, bitter) via GPRC6A; GPRC6A antagonists abolish ornithine-enhanced taste preferences and chorda tympani nerve responses; immunohistochemistry shows GPRC6A expression in type II taste cells of fungiform papillae. Two-bottle preference test, chorda tympani nerve recording, GPRC6A antagonist treatment, immunohistochemistry eLife Medium 40309958
2025 GPRC6A activates mTORC1 signaling in tauopathy contexts; overexpression of GPRC6A or arginine supplementation independently activates mTORC1 and promotes tau accumulation in cell culture; genetic reduction or pharmacological antagonism of GPRC6A reduces tau accumulation, phosphorylation, and oligomerization. GPRC6A overexpression, genetic knockdown, pharmacological antagonism, mTORC1/tau phosphorylation assays in cell models Neurobiology of disease Medium 40848921
2015 GPRC6A mediates alum-induced NLRP3 inflammasome activation; GPRC6A-/- macrophages show reduced alum-induced inflammasome activation in vitro and in vivo; GPRC6A is expressed in B cells and its loss leads to increased IgG1 and IL-10 production, demonstrating a dual role in innate and adaptive immune responses. GPRC6A-/- mouse inflammasome activation assay, B cell culture, cytokine/antibody measurement Scientific reports Medium 26602597
2017 GPRC6A-KGKY (human ICL3 polymorphism) expressed in PC-3 prostate cancer cells preferentially activates mTOR compared to ERK signaling relative to mouse GPRC6A-RKLP in HEK-293 cells; CRISPR/Cas9 targeting of GPRC6A in PC-3 cells blocks osteocalcin-stimulated ERK/AKT/mTOR, cell proliferation, migration, and testosterone biosynthesis gene upregulation; GPRC6A-deficient PC-3 xenografts show reduced growth. CRISPR/Cas9 KO in PC-3 cells, xenograft mouse model, signaling pathway analysis, proliferation/migration assays Journal of experimental & clinical cancer research High 28659174
2008 GPRC6A receptors are present on endothelial cells and myocytes of rat mesenteric arteries; activation by L-ornithine or Al3+ induces endothelium-dependent myocyte hyperpolarization sensitive to TRAM-34 (IK(Ca) blocker), suggesting GPRC6A activates intermediate-conductance Ca2+-sensitive K+ channels; anti-GPRC6A antibody blocked these hyperpolarizations. Electrophysiology (myocyte hyperpolarization), pharmacological blockade, anti-GPRC6A antibody, immunohistochemistry, Western blot Cell calcium Medium 18221783
2026 Engineering of the GPRC6A signal peptide and modification of the ICL3 region markedly improved membrane expression of human GPRC6A; negative-staining EM and 2D classification revealed particle architecture consistent with canonical class C GPCRs, providing first direct structural visualization of hGPRC6A. Recombinant protein engineering, mammalian cell expression, detergent purification, negative-staining electron microscopy, 2D classification Protein and peptide letters Medium 41968749

Source papers

Stage 0 corpus · 83 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. PloS one 196 19050760
2013 Osteocalcin promotes β-cell proliferation during development and adulthood through Gprc6a. Diabetes 189 24009262
2011 GPRC6A mediates responses to osteocalcin in β-cells in vitro and pancreas in vivo. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 181 21425331
2004 Deorphanization of GPRC6A: a promiscuous L-alpha-amino acid receptor with preference for basic amino acids. Molecular pharmacology 169 15576628
2010 GPRC6A mediates the non-genomic effects of steroids. The Journal of biological chemistry 145 20947496
2012 The G protein-coupled receptor family C group 6 subtype A (GPRC6A) receptor is involved in amino acid-induced glucagon-like peptide-1 secretion from GLUTag cells. The Journal of biological chemistry 131 23269670
2004 Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor. Gene 130 15194188
2016 Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells. Endocrinology 95 27007074
2014 The GPCR, class C, group 6, subtype A (GPRC6A) receptor: from cloning to physiological function. British journal of pharmacology 93 24032653
2016 GPRC6A: Jack of all metabolism (or master of none). Molecular metabolism 74 28180060
2012 Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks. Endocrinology 74 22374969
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2007 Pharmacological characterization of mouse GPRC6A, an L-alpha-amino-acid receptor modulated by divalent cations. British journal of pharmacology 69 17245368
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2013 Delineation of the GPRC6A receptor signaling pathways using a mammalian cell line stably expressing the receptor. The Journal of pharmacology and experimental therapeutics 61 24008333
2008 No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions. Journal of molecular endocrinology 59 19103720
2017 CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model. Journal of experimental & clinical cancer research : CR 56 28659174
2019 Lysine Enhances the Stimulation of Fatty Acids on Milk Fat Synthesis via the GPRC6A-PI3K-FABP5 Signaling in Bovine Mammary Epithelial Cells. Journal of agricultural and food chemistry 55 31174423
2015 Structural and Functional Evidence for Testosterone Activation of GPRC6A in Peripheral Tissues. Molecular endocrinology (Baltimore, Md.) 54 26440882
2009 Molecular determinants of non-competitive antagonist binding to the mouse GPRC6A receptor. Cell calcium 52 19836834
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2012 The L-α-amino acid receptor GPRC6A is expressed in the islets of Langerhans but is not involved in L-arginine-induced insulin release. Amino acids 46 22714012
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2022 Quercetin Attenuates Osteoporosis in Orchiectomy Mice by Regulating Glucose and Lipid Metabolism via the GPRC6A/AMPK/mTOR Signaling Pathway. Frontiers in endocrinology 38 35547008
2016 Osteocalcin and Sex Hormone Binding Globulin Compete on a Specific Binding Site of GPRC6A. Endocrinology 38 27673554
2008 Evidence for the presence of GPRC6A receptors in rat mesenteric arteries. Cell calcium 38 18221783
2019 Membrane androgen receptors (OXER1, GPRC6A AND ZIP9) in prostate and breast cancer: A comparative study of their expression. Steroids 35 30707908
2012 Replication and fine mapping for association of the C2orf43, FOXP4, GPRC6A and RFX6 genes with prostate cancer in the Chinese population. PloS one 35 22662242
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2016 Polymorphism rs2274911 of GPRC6A as a Novel Risk Factor for Testis Failure. The Journal of clinical endocrinology and metabolism 34 26735260
2013 Increased susceptibility to diet-induced obesity in GPRC6A receptor knockout mice. The Journal of endocrinology 34 23428581
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2014 Testosterone stimulates Duox1 activity through GPRC6A in skin keratinocytes. The Journal of biological chemistry 32 25164816
2017 The GPRC6A receptor displays constitutive internalization and sorting to the slow recycling pathway. The Journal of biological chemistry 30 28280242
2019 Human GPRC6A Mediates Testosterone-Induced Mitogen-Activated Protein Kinases and mTORC1 Signaling in Prostate Cancer Cells. Molecular pharmacology 28 30894404
2015 GPRC6A mediates Alum-induced Nlrp3 inflammasome activation but limits Th2 type antibody responses. Scientific reports 26 26602597
2020 Pharmacology and physiological function of the orphan GPRC6A receptor. Basic & clinical pharmacology & toxicology 25 32056382
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2021 Explaining Divergent Observations Regarding Osteocalcin/GPRC6A Endocrine Signaling. Endocrinology 22 33474566
2022 L-arginine stimulates the proliferation of mouse mammary epithelial cells and the development of mammary gland in pubertal mice by activating the GPRC6A/PI3K/AKT/mTOR signalling pathway. Journal of animal physiology and animal nutrition 21 35616019
2016 Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function. The Journal of biological chemistry 21 27986810
2021 Osteocalcin Alleviates Nonalcoholic Fatty Liver Disease in Mice through GPRC6A. International journal of endocrinology 19 33531899
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2015 GPRC6a is not required for the effects of a high-protein diet on body weight in mice. Obesity (Silver Spring, Md.) 19 25958858
2006 Known regulators of nitric oxide synthase and arginase are agonists at the human G-protein-coupled receptor GPRC6A. British journal of pharmacology 19 16491104
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2018 Computationally identified novel agonists for GPRC6A. PloS one 17 29684031
2021 Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis. The Journal of biological chemistry 16 33428938
2021 Undercarboxylated osteocalcin inhibits the early differentiation of osteoclast mediated by Gprc6a. PeerJ 16 33717684
2016 Evidence for a role of GPRC6A in prostate cancer metastasis based on case-control and in vitro analyses. European review for medical and pharmacological sciences 16 27338047
2015 Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold. Journal of medicinal chemistry 16 26516782
2013 Enhanced voluntary wheel running in GPRC6A receptor knockout mice. Physiology & behavior 16 23680430
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2022 RS 2247911 polymorphism of GPRC6A gene and serum undercarboxylated-osteocalcin are associated with testis function. Journal of endocrinological investigation 7 35482214
2021 Uncarboxylated osteocalcin reverses the high glucose‑induced inhibition of the osteogenic differentiation of MC3T3E1 cells via the GPRC6A/cAMP/PKA/AMPK signaling pathway. International journal of molecular medicine 7 33786607
2019 SHBG141-161 Domain-Peptide Stimulates GPRC6A-Mediated Response in Leydig and β-Langerhans cell lines. Scientific reports 6 31857654
2022 GPRC6A is a key mediator of palmitic acid regulation of lipid synthesis in bovine mammary epithelial cells. Cell biology international 5 35979663
2022 GPRC6A Mediates Glucose and Amino Acid Homeostasis in Mice. Metabolites 5 36005612
2025 LC-MS/MS assay to confirm that the endogenous metabolite L-Arginine promotes trophoblast invasion in the placenta accreta spectrum through upregulation of the GPRC6A/PI3K/AKT pathway. BMC pregnancy and childbirth 4 40197285
2024 Testosterone acts through the membrane protein GPRC6A to cause cardiac edema in zebrafish embryos. Development (Cambridge, England) 4 39479956
2022 Untargeted Metabolomics Reveals the Function of GPRC6A in Amino Acid and Lipid Metabolism in Mice. Metabolites 4 36144181
2022 Extracellular Ca2+ aggravates IgE-induced allergic reaction in mast cells through GPRC6A, a novel family C G-protein-coupled receptor. Life sciences 4 36257460
2020 rs2274911 polymorphism in GPRC6A associated with serum E2 and PSA in a Southern Chinese male population. Gene 4 32827681
2017 Adiponectin receptor 1 resists the decline of serum osteocalcin and GPRC6A expression in ovariectomized mice. PloS one 4 29194451
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2025 GPRC6A as a novel kokumi receptor responsible for enhanced taste preferences by ornithine. eLife 1 40309958
2025 Undercarboxylated OCN Inhibits Chondrocyte Hypertrophy and Osteoarthritis Development through GPRC6A/HIF-1α Cascade. International journal of biological sciences 1 40765832
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2026 Enhanced Cell Surface Expression Enables Purification and Structural Characterization of Human GPRC6A. Protein and peptide letters 0 41968749
2025 G-Protein-Coupled Receptor Class C Group 6 Member A (GPRC6A) and Serine Protease Inhibitor, Kazal Type 1 (SPINK1) Genotypes Associated With Refractory Functional Dyspepsia: A Potential Link to Endosonographic Features. Cureus 0 40827182
2025 Nutrient sensing receptor GPRC6A regulates mTORC1 signaling and Tau biology. Neurobiology of disease 0 40848921
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2024 GPRC6A is a Potential Therapeutic Target for Metformin Regulation of Glucose Homeostasis in Mice. bioRxiv : the preprint server for biology 0 39229180