GPC6A_HUMAN
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 03-AUG-2022, entry version 144.
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 amino acids with a preference for basic
CC amino acids such as L-Lys, L-Arg and L-ornithine but also by small and
CC polar amino acids. The L-alpha amino acids respond is augmented by
CC divalent cations Ca(2+) and Mg(2+). Activated by extracellular calcium
CC and osteocalcin. Seems to act through a G(q)/G(11) and G(i)-coupled
CC pathway. Mediates the non-genomic effects of androgens in multiple
CC tissue. May coordinate nutritional and hormonal anabolic signals
CC through the sensing of extracellular amino acids, osteocalcin, divalent
CC ions and its responsiveness to anabolic steroids.
CC {ECO:0000269|PubMed:15576628, ECO:0000269|PubMed:20947496}.
CC -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000269|PubMed:25617829}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Multi-pass membrane
CC protein {ECO:0000250}.
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 -!- PTM: N-glycosylated. {ECO:0000250}.
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};
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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 GlyGen; Q5T6X5; 9 sites.
DR iPTMnet; Q5T6X5; -.
DR PhosphoSitePlus; Q5T6X5; -.
DR BioMuta; GPRC6A; -.
DR DMDM; 74745292; -.
DR PaxDb; Q5T6X5; -.
DR PeptideAtlas; Q5T6X5; -.
DR PRIDE; Q5T6X5; -.
DR ProteomicsDB; 64622; -. [Q5T6X5-1]
DR ProteomicsDB; 64623; -. [Q5T6X5-2]
DR ProteomicsDB; 64624; -. [Q5T6X5-3]
DR Antibodypedia; 19443; 285 antibodies from 27 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 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; VFIITDQ; -.
DR OrthoDB; 119538at2759; -.
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; 11 hits in 1068 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 adrenal tissue and 13 other tissues.
DR Genevisible; Q5T6X5; HS.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central.
DR GO; GO:0043200; P:response to amino acid; IDA:UniProtKB.
DR Gene3D; 2.10.50.30; -; 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; PTHR24061; 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; SSF53822; 1.
DR PROSITE; PS00980; G_PROTEIN_RECEP_F3_2; 1.
DR PROSITE; PS50259; G_PROTEIN_RECEP_F3_4; 1.
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
