GPRC6 receptor | Class C Orphans | IUPHAR/BPS Guide to PHARMACOLOGY

GPRC6 receptor

Target id: 55

Nomenclature: GPRC6 receptor

Family: Class C Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for GPRC6 receptor in GtoImmuPdb

Gene and Protein Information
class C G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 926 6q22.31 GPRC6A G protein-coupled receptor class C group 6 member A 7,9
Mouse 7 928 10 B3 Gprc6a G protein-coupled receptor, family C, group 6, member A 9
Rat 7 928 20q11 Gprc6a G protein-coupled receptor, class C, group 6, member A 8
Previous and Unofficial Names
GPCR6A | G protein-coupled receptor, family C, group 6, member A | G protein-coupled receptor, class C, group 6, member A | G protein-coupled receptor
Database Links
Specialist databases
GPCRDB gpc6a_human (Hs), gpc6a_mouse (Mm), gpc6a_rat (Rn)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
L-arginine Hs Full agonist 4.4 pEC50 9
pEC50 4.4 [9]
L-ornithine Hs Full agonist 4.0 pEC50 9
pEC50 4.0 [9]
L-alanine Hs Full agonist 3.8 pEC50 9
pEC50 3.8 [9]
L-lysine Hs Full agonist 3.8 pEC50 9
pEC50 3.8 [9]
L-citrulline Hs Full agonist 3.6 pEC50 9
pEC50 3.6 [9]
glycine Hs Full agonist 3.6 pEC50 9
pEC50 3.6 [9]
L-glutamine Hs Full agonist 3.2 pEC50 9
pEC50 3.2 [9]
L-serine Hs Full agonist 3.2 pEC50 9
pEC50 3.2 [9]
Agonist Comments
The values listed are pEC50 values of a chimeric receptor containing the agonist binding amino-terminal domain from GPRC6A and the 7TM domain from the orthologous goldfish 5.24 receptor. The 5.24 receptor is also a promiscuous L-alpha-amino acid receptor with preference for basic amino acids [6].

The divalent cations calcium and magnesium have been shown to either positively modulate the responses of L-alpha amino acids [3] or to directly activate GPRC6A (≥ 20mM concentration needed for robust responses) [4].

It has been suggested that uncarboxylated osteocalcin is a calcium-dependent agonist; however, the signaling pathway activated remains inconclusive [4-5]. Another study has been unable to confirm the agonist activity of osteocalcin [2].
Antagonist Comments
No antagonists identified so far.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
NPS 2143 Mm Negative ~5.0 pIC50 1
pIC50 ~5.0 (IC50 ~1x10-5 M) [1]
Description: This is an inferred IC50 based on 10µM of the compound inhibiting maximum L-ornithine-induced activation of GPCR6 by approximately 50% (see Fig 1B in reference).
calindol Mm Negative ~5.0 pIC50 1
pIC50 ~5.0 (IC50 ~1x10-5 M) [1]
Description: This is an inferred IC50 based on 10µM of the compound inhibiting maximum L-ornithine-induced activation of GPCR6 by approximately 50% (see Fig 1B in reference).
Allosteric Modulator Comments
NPS 2143 and calindol are ~30 fold more potent on the calcium-sensing receptor (CaS) and thus have limited usability as pharmacological tools.
Primary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
Comments:  Gq/G11-mediated signalling stimulates phospholipase C and increases inositol phosphate generation: determined by stable expression of mouse receptor in Chinese hamster ovary cells. The Gq inhibitor UBO-QIC and phospholipase C inhibitor U73122 both fully inhibit the observed response.
References:  2,9
Tissue Distribution
High expression in adult brain, skeletal muscle, testis and leukocytes.
Medium expression in adult liver, heart, kidney and spleen.
Low expression in the adult lung pancreas, placenta and ovary.
Not detectable in adult thymus, prostate, small intestine and colon.
Species:  Human
Technique:  RT-PCR
References:  7
Highest levels found in the heart, lung, spleen and liver.
Lower levels in the muscle, kidney, brain and testis.
Species:  Mouse
Technique:  RT-PCR
References:  3
Highest expression found in kidney, lung, liver, brain and geschmacksstreifen.
Species:  Rat
Technique:  RT-PCR
References:  8
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of intracellular calcium concentration when the chimeric receptor (GPRC6A and goldfish 5.26 receptor) is expressed in HEK 293-tsA cells.
Species:  Human
Tissue:  HEK 293-tsA cells.
Response measured:  Increase in intracellular calcium.
References:  9
Measurement of inositol-mono-phosphate generation in Chinese hamster ovary cells stably expressing the mouse GPRC6A receptor.
Species:  Mouse
Tissue:  Chinese hamster ovary cells stably expressing the mouse GPRC6A receptor
Response measured:  Inostitol-mono-phosphate generation.
References:  2
Measurement of calcium-activated chloride currents when the chimeric receptor (GPRC6A and goldfish 5.26 receptor) is expressed in Xenopus oocytes.
Species:  Human
Tissue:  Xenopus oocytes transfected with the receptor chimer.
Response measured:  Strong inward chloride current.
References:  9
Measurement of calcium-activated chloride current in Xenopus oocytes transfected with the wild-type mouse GPRC6A receptor.
Species:  Mouse
Tissue:  Xenopus oocytes transfected with mouse GPRC6A receptors.
Response measured:  Strong inward chloride current.
References:  9
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0002896 abnormal bone mineralization PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0005418 abnormal circulating hormone level PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0001565 abnormal circulating phosphate level PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0009199 abnormal external male genitalia morphology PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0002078 abnormal glucose homeostasis PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0005291 abnormal glucose tolerance PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0009205 abnormal internal male genitalia morphology PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0000628 abnormal mammary gland development PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0009643 abnormal urine homeostasis PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0002727 decreased circulating insulin level PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0002780 decreased circulating testosterone level PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0003961 decreased lean body mass PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0001935 decreased litter size PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0004910 decreased seminal vesicle weight PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0004852 decreased testis weight PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0002628 hepatic steatosis PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0005441 hypercalciuria PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0002901 hyperphosphaturia PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0005182 increased circulating estradiol level PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0005559 increased circulating glucose level PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0002891 increased insulin sensitivity PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0000008 increased white adipose tissue amount PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0005160 proteinuria PMID: 19050760 
Gprc6atm1Ldq Gprc6atm1Ldq/Gprc6atm1Ldq
involves: 129X1/SvJ * C57BL/6
MGI:2429498  MP:0001147 small testis PMID: 19050760 
General Comments
The human receptor does not traffic to the cell surface [7] and it has thus not been possible to obtain a functional signal from the wild-type receptor [9]. When expressing a chimeric receptor containing the agonist binding amino-terminal domain from GPRC6A and the 7TM domain from the orthologous goldfish 5.24 receptor [6] it does traffic to the cell surface and respond to agonists.
The mouse Gprc6a receptor does traffic to the cell surface and respond to agonists when expressed in Xenopus oocytes as a wild-type (and so does not require the production of chimeric receptors) [9]. Both mouse and rat Gprc6a receptors traffic to the cell surface when expressed in HEK293-taA cells [8].

References

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1. Faure H, Gorojankina T, Rice N, Dauban P, Dodd RH, Bräuner-Osborne H, Rognan D, Ruat M. (2009) Molecular determinants of non-competitive antagonist binding to the mouse GPRC6A receptor. Cell Calcium, 46 (5-6): 323-32. [PMID:19836834]

2. Jacobsen SE, Nørskov-Lauritsen L, Thomsen AR, Smajilovic S, Wellendorph P, Larsson NH, Lehmann A, Bhatia VK, Bräuner-Osborne H. (2013) Delineation of the GPRC6A receptor signaling pathways using a mammalian cell line stably expressing the receptor. J. Pharmacol. Exp. Ther., 347 (2): 298-309. [PMID:24008333]

3. Kuang D, Yao Y, Lam J, Tsushima RG, Hampson DR. (2005) Cloning and characterization of a family C orphan G-protein coupled receptor. J Neurochem, 93: 383-391. [PMID:15816861]

4. Pi M, Faber P, Ekema G, Jackson PD, Ting A, Wang N, Fontilla-Poole M, Mays RW, Brunden KR, Harrington JJ, Quarles LD. (2005) Identification of a Novel Extracellular Cation-sensing G-protein-coupled Receptor. J Biol Chem, 280: 40201-40209. [PMID:16199532]

5. Pi M, Wu Y, Quarles LD. (2011) GPRC6A mediates responses to osteocalcin in β-cells in vitro and pancreas in vivo. J. Bone Miner. Res., 26 (7): 1680-3. [PMID:21425331]

6. Speca DJ, Lin DM, Sorensen PW, Isacoff EY, Ngai J, Dittman AH. (1999) Functional identification of a goldfish odorant receptor. Neuron, 23: 487-489. [PMID:10433261]

7. Wellendorph P, Brauner-Osborne H. (2004) Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor. Gene, 335: 37-46. [PMID:15194188]

8. Wellendorph P, Burhenne N, Christiansen B, Walter B, Schmale H, Bräuner-Osborne H. (2007) The rat GPRC6A: cloning and characterization. Gene, 396 (2): 257-67. [PMID:17478059]

9. Wellendorph P, Hansen KB, Balsgaard A, Greenwood JR, Egebjerg J, Brauner-Osborne H. (2005) Deorphanization of GPRC6A: a promiscuous L-alpha-amino acid receptor with preference for basic amino acids. Mol Pharmacol., 67: 589-597. [PMID:15576628]

Contributors

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How to cite this page

Hans Bräuner-Osborne, Daniel Bikle, Edward M. Brown, Arthur Conigrave, Dolores Shoback.
Class C Orphans: GPRC6 receptor. Last modified on 20/02/2018. Accessed on 14/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=55.