ID GPC6A_HUMAN Reviewed; 926 AA. AC Q5T6X5; Q6JK43; Q6JK44; Q8NGU8; Q8NHZ9; Q8TDT6; DT 06-DEC-2005, integrated into UniProtKB/Swiss-Prot. DT 21-DEC-2004, sequence version 1. DT 27-MAR-2024, entry version 153. DE RecName: Full=G-protein coupled receptor family C group 6 member A; DE Short=hGPRC6A; DE AltName: Full=G-protein coupled receptor GPCR33; DE Short=hGPCR33; DE Flags: Precursor; GN Name=GPRC6A; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), TISSUE SPECIFICITY, AND RP VARIANT SER-91. RC TISSUE=Kidney; RX PubMed=15194188; DOI=10.1016/j.gene.2004.03.003; RA Wellendorph P., Braeuner-Osborne H.; RT "Molecular cloning, expression, and sequence analysis of GPRC6A, a novel RT family C G-protein-coupled receptor."; RL Gene 335:37-46(2004). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT SER-91. RC TISSUE=Kidney; RA Lorenz-Depiereux B., Dorner M., Strom T.M.; RT "Cloning of a metabotropic glutamate/pheromone receptor (GPRC6A)."; RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 66-926. RA Suwa M., Sato T., Okouchi I., Arita M., Futami K., Matsumoto S., RA Tsutsumi S., Aburatani H., Asai K., Akiyama Y.; RT "Genome-wide discovery and analysis of human seven transmembrane helix RT receptor genes."; RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 559-926. RX PubMed=12044878; DOI=10.1016/s0014-5793(02)02775-8; RA Takeda S., Kadowaki S., Haga T., Takaesu H., Mitaku S.; RT "Identification of G protein-coupled receptor genes from the human genome RT sequence."; RL FEBS Lett. 520:97-101(2002). RN [6] RP FUNCTION, AND MUTAGENESIS OF SER-149 AND THR-172. RX PubMed=15576628; DOI=10.1124/mol.104.007559; RA Wellendorph P., Hansen K.B., Balsgaard A., Greenwood J.R., Egebjerg J., RA Brauener-Osborne H.; RT "Deorphanization of GPRC6A: a promiscuous L-alpha-amino acid receptor with RT preference for basic amino acids."; RL Mol. Pharmacol. 67:589-597(2005). RN [7] RP FUNCTION. RX PubMed=20947496; DOI=10.1074/jbc.m110.158063; RA Pi M., Parrill A.L., Quarles L.D.; RT "GPRC6A mediates the non-genomic effects of steroids."; RL J. Biol. Chem. 285:39953-39964(2010). RN [8] RP SUBUNIT, DISULFIDE BOND, AND GLYCOSYLATION AT ASN-121; ASN-259; ASN-332; RP ASN-378; ASN-452; ASN-555 AND ASN-567. RX PubMed=25617829; DOI=10.1016/j.febslet.2015.01.019; RA Norskov-Lauritsen L., Jorgensen S., Brauner-Osborne H.; RT "N-glycosylation and disulfide bonding affects GPRC6A receptor expression, RT function, and dimerization."; RL FEBS Lett. 589:588-597(2015). CC -!- FUNCTION: Receptor activated by multiple ligands, including osteocalcin CC (BGLAP), basic amino acids, and various cations (PubMed:15576628). CC Activated by amino acids with a preference for basic amino acids such CC as L-Lys, L-Arg and L-ornithine but also by small and polar amino acids CC (PubMed:15576628). The L-alpha amino acids respond is augmented by CC divalent cations Ca(2+) and Mg(2+) (By similarity). Seems to act CC through a G(q)/G(11) and G(i)-coupled pathway (By similarity). CC Regulates testosterone production by acting as a ligand for CC uncarboxylated osteocalcin hormone: osteocalcin-binding at the surface CC of Leydig cells initiates a signaling response that promotes the CC expression of enzymes required for testosterone synthesis in a CREB- CC dependent manner (By similarity). Mediates the non-genomic effects of CC androgens in multiple tissue (By similarity). May coordinate CC nutritional and hormonal anabolic signals through the sensing of CC extracellular amino acids, osteocalcin, divalent ions and its CC responsiveness to anabolic steroids (PubMed:20947496). CC {ECO:0000250|UniProtKB:Q8K4Z6, ECO:0000269|PubMed:15576628, CC ECO:0000269|PubMed:20947496}. CC -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000269|PubMed:25617829}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q8K4Z6}; CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q8K4Z6}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q5T6X5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q5T6X5-2; Sequence=VSP_016454; CC Name=3; CC IsoId=Q5T6X5-3; Sequence=VSP_016455; CC -!- TISSUE SPECIFICITY: Isoform 1 is expressed at high level in brain, CC skeletal muscle, testis, bone, calvaria, osteoblasts and leukocytes. CC Expressed at intermediate level in liver, heart, kidney and spleen. CC Expressed at low level in lung, pancreas, placenta and ovary. Not CC detected in thymus, prostate, small intestine, tongue and colon. CC Isoform 1 and isoform 2 are expressed in kidney at the same level. CC Isoform 2 is expressed at lower level than isoform 1 in the other CC tissues. {ECO:0000269|PubMed:15194188}. CC -!- MISCELLANEOUS: [Isoform 1]: Major isoform. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 3 family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAC05904.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY435125; AAS13465.1; -; mRNA. DR EMBL; AY435126; AAS13466.1; -; mRNA. DR EMBL; AY435127; AAS13467.1; -; mRNA. DR EMBL; AF502962; AAM22230.1; -; mRNA. DR EMBL; AL354716; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AB065680; BAC05904.1; ALT_SEQ; Genomic_DNA. DR EMBL; AB083615; BAB89328.1; -; Genomic_DNA. DR CCDS; CCDS5112.1; -. [Q5T6X5-1] DR CCDS; CCDS69184.1; -. [Q5T6X5-3] DR CCDS; CCDS69185.1; -. [Q5T6X5-2] DR RefSeq; NP_001273283.1; NM_001286354.1. [Q5T6X5-2] DR RefSeq; NP_001273284.1; NM_001286355.1. [Q5T6X5-3] DR RefSeq; NP_683766.2; NM_148963.3. [Q5T6X5-1] DR AlphaFoldDB; Q5T6X5; -. DR SMR; Q5T6X5; -. DR STRING; 9606.ENSP00000309493; -. DR ChEMBL; CHEMBL4523873; -. DR DrugCentral; Q5T6X5; -. DR GuidetoPHARMACOLOGY; 55; -. DR TCDB; 9.A.14.7.3; the g-protein-coupled receptor (gpcr) family. DR GlyCosmos; Q5T6X5; 9 sites, No reported glycans. DR GlyGen; Q5T6X5; 9 sites. DR iPTMnet; Q5T6X5; -. DR PhosphoSitePlus; Q5T6X5; -. DR BioMuta; GPRC6A; -. DR DMDM; 74745292; -. DR PaxDb; 9606-ENSP00000309493; -. DR PeptideAtlas; Q5T6X5; -. DR ProteomicsDB; 64622; -. [Q5T6X5-1] DR ProteomicsDB; 64623; -. [Q5T6X5-2] DR ProteomicsDB; 64624; -. [Q5T6X5-3] DR Antibodypedia; 19443; 319 antibodies from 28 providers. DR DNASU; 222545; -. DR Ensembl; ENST00000310357.8; ENSP00000309493.4; ENSG00000173612.10. [Q5T6X5-1] DR Ensembl; ENST00000368549.7; ENSP00000357537.3; ENSG00000173612.10. [Q5T6X5-3] DR Ensembl; ENST00000530250.1; ENSP00000433465.1; ENSG00000173612.10. [Q5T6X5-2] DR GeneID; 222545; -. DR KEGG; hsa:222545; -. DR MANE-Select; ENST00000310357.8; ENSP00000309493.4; NM_148963.4; NP_683766.2. DR UCSC; uc003pxj.3; human. [Q5T6X5-1] DR AGR; HGNC:18510; -. DR CTD; 222545; -. DR DisGeNET; 222545; -. DR GeneCards; GPRC6A; -. DR HGNC; HGNC:18510; GPRC6A. DR HPA; ENSG00000173612; Not detected. DR MIM; 613572; gene. DR neXtProt; NX_Q5T6X5; -. DR OpenTargets; ENSG00000173612; -. DR PharmGKB; PA38342; -. DR VEuPathDB; HostDB:ENSG00000173612; -. DR eggNOG; KOG1056; Eukaryota. DR GeneTree; ENSGT00940000158416; -. DR HOGENOM; CLU_005389_1_0_1; -. DR InParanoid; Q5T6X5; -. DR OMA; ICFICAF; -. DR OrthoDB; 4224743at2759; -. DR PhylomeDB; Q5T6X5; -. DR TreeFam; TF331269; -. DR PathwayCommons; Q5T6X5; -. DR Reactome; R-HSA-416476; G alpha (q) signalling events. DR Reactome; R-HSA-420499; Class C/3 (Metabotropic glutamate/pheromone receptors). DR BioGRID-ORCS; 222545; 12 hits in 1145 CRISPR screens. DR GeneWiki; GPRC6A; -. DR GenomeRNAi; 222545; -. DR Pharos; Q5T6X5; Tchem. DR PRO; PR:Q5T6X5; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q5T6X5; Protein. DR Bgee; ENSG00000173612; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 13 other cell types or tissues. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0004930; F:G protein-coupled receptor activity; ISS:UniProtKB. DR GO; GO:2000224; P:regulation of testosterone biosynthetic process; ISS:UniProtKB. DR GO; GO:0043200; P:response to amino acid; IDA:UniProtKB. DR CDD; cd06361; PBP1_GPC6A-like; 1. DR Gene3D; 3.40.50.2300; -; 2. DR Gene3D; 2.10.50.30; GPCR, family 3, nine cysteines domain; 1. DR InterPro; IPR001828; ANF_lig-bd_rcpt. DR InterPro; IPR000337; GPCR_3. DR InterPro; IPR011500; GPCR_3_9-Cys_dom. DR InterPro; IPR038550; GPCR_3_9-Cys_sf. DR InterPro; IPR017978; GPCR_3_C. DR InterPro; IPR000068; GPCR_3_Ca_sens_rcpt-rel. DR InterPro; IPR017979; GPCR_3_CS. DR InterPro; IPR028082; Peripla_BP_I. DR PANTHER; PTHR24061; CALCIUM-SENSING RECEPTOR-RELATED; 1. DR PANTHER; PTHR24061:SF5; G-PROTEIN COUPLED RECEPTOR FAMILY C GROUP 6 MEMBER A; 1. DR Pfam; PF00003; 7tm_3; 1. DR Pfam; PF01094; ANF_receptor; 1. DR Pfam; PF07562; NCD3G; 1. DR PRINTS; PR00592; CASENSINGR. DR PRINTS; PR00248; GPCRMGR. DR SUPFAM; SSF53822; Periplasmic binding protein-like I; 1. DR PROSITE; PS00980; G_PROTEIN_RECEP_F3_2; 1. DR PROSITE; PS50259; G_PROTEIN_RECEP_F3_4; 1. DR Genevisible; Q5T6X5; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Disulfide bond; KW G-protein coupled receptor; Glycoprotein; Membrane; Receptor; KW Reference proteome; Signal; Transducer; Transmembrane; Transmembrane helix. FT SIGNAL 1..18 FT /evidence="ECO:0000255" FT CHAIN 19..926 FT /note="G-protein coupled receptor family C group 6 member FT A" FT /id="PRO_0000043196" FT TOPO_DOM 19..594 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 595..615 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TOPO_DOM 616..631 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 632..652 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TOPO_DOM 653..669 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 670..690 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 691..704 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 705..725 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TOPO_DOM 726..748 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 749..769 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TOPO_DOM 770..782 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 783..803 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TOPO_DOM 804..810 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 811..831 FT /note="Helical; Name=7" FT /evidence="ECO:0000255" FT TOPO_DOM 832..926 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT CARBOHYD 121 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:25617829" FT CARBOHYD 259 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:25617829" FT CARBOHYD 332 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:25617829" FT CARBOHYD 378 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:25617829" FT CARBOHYD 452 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:25617829" FT CARBOHYD 555 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:25617829" FT CARBOHYD 567 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:25617829" FT CARBOHYD 590 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 733 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 131 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:25617829" FT VAR_SEQ 271..445 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15194188" FT /id="VSP_016454" FT VAR_SEQ 446..516 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15194188" FT /id="VSP_016455" FT VARIANT 91 FT /note="P -> S (in dbSNP:rs2274911)" FT /evidence="ECO:0000269|PubMed:15194188, ECO:0000269|Ref.2" FT /id="VAR_023966" FT VARIANT 144 FT /note="I -> R (in dbSNP:rs28360548)" FT /id="VAR_049283" FT VARIANT 599 FT /note="I -> T (in dbSNP:rs35937022)" FT /id="VAR_061203" FT MUTAGEN 149 FT /note="S->A: Loss of function." FT /evidence="ECO:0000269|PubMed:15576628" FT MUTAGEN 172 FT /note="T->A: Loss of function." FT /evidence="ECO:0000269|PubMed:15576628" SQ SEQUENCE 926 AA; 104753 MW; 2019C884FF092EEF CRC64; MAFLIILITC FVIILATSQP CQTPDDFVAA TSPGHIIIGG LFAIHEKMLS SEDSPRRPQI QECVGFEISV FLQTLAMIHS IEMINNSTLL PGVKLGYEIY DTCTEVTVAM AATLRFLSKF NCSRETVEFK CDYSSYMPRV KAVIGSGYSE ITMAVSRMLN LQLMPQVGYE STAEILSDKI RFPSFLRTVP SDFHQIKAMA HLIQKSGWNW IGIITTDDDY GRLALNTFII QAEANNVCIA FKEVLPAFLS DNTIEVRINR TLKKIILEAQ VNVIVVFLRQ FHVFDLFNKA IEMNINKMWI ASDNWSTATK ITTIPNVKKI GKVVGFAFRR GNISSFHSFL QNLHLLPSDS HKLLHEYAMH LSACAYVKDT DLSQCIFNHS QRTLAYKANK AIERNFVMRN DFLWDYAEPG LIHSIQLAVF ALGYAIRDLC QARDCQNPNA FQPWELLGVL KNVTFTDGWN SFHFDAHGDL NTGYDVVLWK EINGHMTVTK MAEYDLQNDV FIIPDQETKN EFRNLKQIQS KCSKECSPGQ MKKTTRSQHI CCYECQNCPE NHYTNQTDMP HCLLCNNKTH WAPVRSTMCF EKEVEYLNWN DSLAILLLIL SLLGIIFVLV VGIIFTRNLN TPVVKSSGGL RVCYVILLCH FLNFASTSFF IGEPQDFTCK TRQTMFGVSF TLCISCILTK SLKILLAFSF DPKLQKFLKC LYRPILIIFT CTGIQVVICT LWLIFAAPTV EVNVSLPRVI ILECEEGSIL AFGTMLGYIA ILAFICFIFA FKGKYENYNE AKFITFGMLI YFIAWITFIP IYATTFGKYV PAVEIIVILI SNYGILYCTF IPKCYVIICK QEINTKSAFL KMIYSYSSHS VSSIALSPAS LDSMSGNVTM TNPSSSGKSA TWQKSKDLQA QAFAHICREN ATSVSKTLPR KRMSSI //