GRM6_HUMAN
ID GRM6_HUMAN Reviewed; 877 AA.
AC O15303;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 16-JUN-2009, sequence version 2.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=Metabotropic glutamate receptor 6;
DE Short=mGluR6;
DE Flags: Precursor;
GN Name=GRM6; Synonyms=GPRC1F, MGLUR6;
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 [GENOMIC DNA], AND VARIANT PRO-59.
RX PubMed=9215706; DOI=10.1111/j.1460-9568.1997.tb01477.x;
RA Hashimoto T., Inazawa J., Okamoto N., Tagawa Y., Bessho Y., Honda Y.,
RA Nakanishi S.;
RT "The whole nucleotide sequence and chromosomal localization of the gene for
RT human metabotropic glutamate receptor subtype 6.";
RL Eur. J. Neurosci. 9:1226-1235(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [3]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=23452348; DOI=10.1111/pcmr.12083;
RA Devi S., Markandeya Y., Maddodi N., Dhingra A., Vardi N., Balijepalli R.C.,
RA Setaluri V.;
RT "Metabotropic glutamate receptor 6 signaling enhances TRPM1 calcium channel
RT function and increases melanin content in human melanocytes.";
RL Pigment Cell Melanoma Res. 26:348-356(2013).
RN [4]
RP VARIANTS CSNB1B SER-150 AND LYS-781.
RX PubMed=15781871; DOI=10.1073/pnas.0501233102;
RA Dryja T.P., McGee T.L., Berson E.L., Fishman G.A., Sandberg M.A.,
RA Alexander K.R., Derlacki D.J., Rajagopalan A.S.;
RT "Night blindness and abnormal cone electroretinogram ON responses in
RT patients with mutations in the GRM6 gene encoding mGluR6.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:4884-4889(2005).
RN [5]
RP VARIANT [LARGE SCALE ANALYSIS] PHE-191.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [6]
RP VARIANTS CSNB1B LEU-46; ARG-58; SER-150; THR-405; TYR-522 AND LYS-781,
RP VARIANT PRO-59, CHARACTERIZATION OF VARIANT PRO-59, CHARACTERIZATION OF
RP VARIANTS CSNB1B LEU-46; ARG-58; SER-150; THR-405; TYR-522 AND LYS-781,
RP SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=17405131; DOI=10.1002/humu.20499;
RA Zeitz C., Forster U., Neidhardt J., Feil S., Kalin S., Leifert D.,
RA Flor P.J., Berger W.;
RT "Night blindness-associated mutations in the ligand-binding, cysteine-rich,
RT and intracellular domains of the metabotropic glutamate receptor 6 abolish
RT protein trafficking.";
RL Hum. Mutat. 28:771-780(2007).
RN [7]
RP VARIANTS CSNB1B LEU-46; ARG-58 AND TYR-522.
RX PubMed=23714322; DOI=10.1016/j.ophtha.2013.03.002;
RA Bijveld M.M., Florijn R.J., Bergen A.A., van den Born L.I., Kamermans M.,
RA Prick L., Riemslag F.C., van Schooneveld M.J., Kappers A.M.,
RA van Genderen M.M.;
RT "Genotype and phenotype of 101 Dutch patients with congenital stationary
RT night blindness.";
RL Ophthalmology 120:2072-2081(2013).
CC -!- FUNCTION: G-protein coupled receptor for glutamate. Ligand binding
CC causes a conformation change that triggers signaling via guanine
CC nucleotide-binding proteins (G proteins) and modulates the activity of
CC down-stream effectors, such as adenylate cyclase. Signaling inhibits
CC adenylate cyclase activity (By similarity). Signaling stimulates TRPM1
CC channel activity and Ca(2+) uptake. Required for normal vision.
CC {ECO:0000250, ECO:0000269|PubMed:23452348}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:17405131}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:17405131};
CC Multi-pass membrane protein {ECO:0000269|PubMed:17405131}. Endoplasmic
CC reticulum membrane {ECO:0000269|PubMed:17405131}; Multi-pass membrane
CC protein {ECO:0000269|PubMed:17405131}. Golgi apparatus membrane
CC {ECO:0000269|PubMed:17405131}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:17405131}. Cell projection, dendrite {ECO:0000250}.
CC Note=Subject to trafficking from the endoplasmic reticulum to the Golgi
CC apparatus and then to the cell membrane.
CC -!- TISSUE SPECIFICITY: Detected in melanocytes.
CC {ECO:0000269|PubMed:23452348}.
CC -!- DISEASE: Night blindness, congenital stationary, 1B (CSNB1B)
CC [MIM:257270]: A non-progressive retinal disorder characterized by
CC impaired night vision. Congenital stationary night blindness type 1B is
CC an autosomal recessive form associated with a negative
CC electroretinogram waveform. Patients are night blind from an early age,
CC and when maximally dark-adapted, they could perceive lights only with
CC an intensity equal to or slightly dimmer than that normally detected by
CC the cone system. ERGs in response to single brief flashes of light have
CC clearly detectable a-waves, which are derived from photoreceptors, and
CC greatly reduced b-waves, which are derived from the second-order inner
CC retinal neurons. ERGs in response to sawtooth flickering light indicate
CC a markedly reduced on response and a nearly normal OFF response. There
CC is no subjective delay in the perception of suddenly appearing white vs
CC black objects on a gray background. {ECO:0000269|PubMed:15781871,
CC ECO:0000269|PubMed:17405131, ECO:0000269|PubMed:23714322}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 3 family.
CC {ECO:0000305}.
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DR EMBL; U82083; AAB82068.1; -; Genomic_DNA.
DR EMBL; AC104117; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS4442.1; -.
DR RefSeq; NP_000834.2; NM_000843.3.
DR AlphaFoldDB; O15303; -.
DR SMR; O15303; -.
DR BioGRID; 109173; 1.
DR STRING; 9606.ENSP00000231188; -.
DR BindingDB; O15303; -.
DR ChEMBL; CHEMBL4573; -.
DR DrugCentral; O15303; -.
DR GuidetoPHARMACOLOGY; 294; -.
DR GlyGen; O15303; 4 sites.
DR iPTMnet; O15303; -.
DR PhosphoSitePlus; O15303; -.
DR BioMuta; GRM6; -.
DR MassIVE; O15303; -.
DR PaxDb; O15303; -.
DR PeptideAtlas; O15303; -.
DR PRIDE; O15303; -.
DR ProteomicsDB; 48571; -.
DR Antibodypedia; 17632; 368 antibodies from 32 providers.
DR DNASU; 2916; -.
DR Ensembl; ENST00000231188.9; ENSP00000231188.5; ENSG00000113262.16.
DR Ensembl; ENST00000517717.3; ENSP00000430767.1; ENSG00000113262.16.
DR Ensembl; ENST00000650031.1; ENSP00000497110.1; ENSG00000113262.16.
DR GeneID; 2916; -.
DR KEGG; hsa:2916; -.
DR MANE-Select; ENST00000517717.3; ENSP00000430767.1; NM_000843.4; NP_000834.2.
DR UCSC; uc003mjr.4; human.
DR CTD; 2916; -.
DR DisGeNET; 2916; -.
DR GeneCards; GRM6; -.
DR HGNC; HGNC:4598; GRM6.
DR HPA; ENSG00000113262; Tissue enriched (retina).
DR MalaCards; GRM6; -.
DR MIM; 257270; phenotype.
DR MIM; 604096; gene.
DR neXtProt; NX_O15303; -.
DR OpenTargets; ENSG00000113262; -.
DR Orphanet; 215; Congenital stationary night blindness.
DR PharmGKB; PA28995; -.
DR VEuPathDB; HostDB:ENSG00000113262; -.
DR eggNOG; KOG1056; Eukaryota.
DR GeneTree; ENSGT01030000234648; -.
DR HOGENOM; CLU_005389_0_0_1; -.
DR InParanoid; O15303; -.
DR OMA; TAVMFNE; -.
DR OrthoDB; 1154468at2759; -.
DR PhylomeDB; O15303; -.
DR TreeFam; TF313240; -.
DR PathwayCommons; O15303; -.
DR Reactome; R-HSA-418594; G alpha (i) signalling events.
DR Reactome; R-HSA-420499; Class C/3 (Metabotropic glutamate/pheromone receptors).
DR SignaLink; O15303; -.
DR SIGNOR; O15303; -.
DR BioGRID-ORCS; 2916; 5 hits in 1066 CRISPR screens.
DR GeneWiki; Metabotropic_glutamate_receptor_6; -.
DR GenomeRNAi; 2916; -.
DR Pharos; O15303; Tchem.
DR PRO; PR:O15303; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; O15303; protein.
DR Bgee; ENSG00000113262; Expressed in pancreatic ductal cell and 94 other tissues.
DR Genevisible; O15303; HS.
DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0035841; C:new growing cell tip; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0045202; C:synapse; IEA:GOC.
DR GO; GO:0001640; F:adenylate cyclase inhibiting G protein-coupled glutamate receptor activity; IBA:GO_Central.
DR GO; GO:0004930; F:G protein-coupled receptor activity; TAS:UniProtKB.
DR GO; GO:0008066; F:glutamate receptor activity; IMP:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB.
DR GO; GO:0007268; P:chemical synaptic transmission; IEA:Ensembl.
DR GO; GO:0050908; P:detection of light stimulus involved in visual perception; IMP:UniProtKB.
DR GO; GO:0009584; P:detection of visible light; TAS:ProtInc.
DR GO; GO:0007216; P:G protein-coupled glutamate receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0007626; P:locomotory behavior; IEA:Ensembl.
DR GO; GO:1905665; P:positive regulation of calcium ion import across plasma membrane; IMP:UniProtKB.
DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IBA:GO_Central.
DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl.
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; IPR000112; GPCR_3__mGluR6.
DR InterPro; IPR017978; GPCR_3_C.
DR InterPro; IPR017979; GPCR_3_CS.
DR InterPro; IPR000162; GPCR_3_mtglu_rcpt.
DR InterPro; IPR028082; Peripla_BP_I.
DR Pfam; PF00003; 7tm_3; 1.
DR Pfam; PF01094; ANF_receptor; 1.
DR Pfam; PF07562; NCD3G; 1.
DR PRINTS; PR00248; GPCRMGR.
DR PRINTS; PR01056; MTABOTROPC6R.
DR PRINTS; PR00593; MTABOTROPICR.
DR SUPFAM; SSF53822; SSF53822; 1.
DR PROSITE; PS00979; G_PROTEIN_RECEP_F3_1; 1.
DR PROSITE; PS00980; G_PROTEIN_RECEP_F3_2; 1.
DR PROSITE; PS00981; G_PROTEIN_RECEP_F3_3; 1.
DR PROSITE; PS50259; G_PROTEIN_RECEP_F3_4; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cell projection; Congenital stationary night blindness;
KW Disease variant; Disulfide bond; Endoplasmic reticulum;
KW G-protein coupled receptor; Glycoprotein; Golgi apparatus; Membrane;
KW Receptor; Reference proteome; Sensory transduction; Signal; Transducer;
KW Transmembrane; Transmembrane helix; Vision.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..877
FT /note="Metabotropic glutamate receptor 6"
FT /id="PRO_0000012934"
FT TOPO_DOM 25..585
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 586..608
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 609..622
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 623..643
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 644..654
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 655..673
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 674..697
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 698..718
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 719..748
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 749..770
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 771..783
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 784..806
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 807..819
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 820..845
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 846..877
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 856..877
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 154
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250"
FT BINDING 175..177
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250"
FT BINDING 225
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250"
FT BINDING 307
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250"
FT BINDING 400
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250"
FT CARBOHYD 296
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 451
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 479
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 567
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 57..99
FT /evidence="ECO:0000250"
FT DISULFID 244..536
FT /evidence="ECO:0000250"
FT DISULFID 367..383
FT /evidence="ECO:0000250"
FT DISULFID 423..430
FT /evidence="ECO:0000250"
FT DISULFID 518..537
FT /evidence="ECO:0000250"
FT DISULFID 522..540
FT /evidence="ECO:0000250"
FT DISULFID 543..555
FT /evidence="ECO:0000250"
FT DISULFID 558..571
FT /evidence="ECO:0000250"
FT VARIANT 46
FT /note="P -> L (in CSNB1B; abolishes expression at the cell
FT membrane; dbSNP:rs62638197)"
FT /evidence="ECO:0000269|PubMed:17405131,
FT ECO:0000269|PubMed:23714322"
FT /id="VAR_069817"
FT VARIANT 58
FT /note="G -> R (in CSNB1B; abolishes expression at the cell
FT membrane; dbSNP:rs62638198)"
FT /evidence="ECO:0000269|PubMed:17405131,
FT ECO:0000269|PubMed:23714322"
FT /id="VAR_069818"
FT VARIANT 59
FT /note="Q -> P (no effect on location at the cell membrane;
FT dbSNP:rs2645329)"
FT /evidence="ECO:0000269|PubMed:17405131,
FT ECO:0000269|PubMed:9215706"
FT /id="VAR_059310"
FT VARIANT 150
FT /note="G -> S (in CSNB1B; abolishes expression at the cell
FT membrane; dbSNP:rs62638202)"
FT /evidence="ECO:0000269|PubMed:15781871,
FT ECO:0000269|PubMed:17405131"
FT /id="VAR_030756"
FT VARIANT 191
FT /note="S -> F (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036195"
FT VARIANT 227
FT /note="E -> V (in dbSNP:rs17078898)"
FT /id="VAR_055876"
FT VARIANT 236
FT /note="I -> F (in dbSNP:rs17078896)"
FT /id="VAR_055877"
FT VARIANT 405
FT /note="I -> T (in CSNB1B; abolishes expression at the cell
FT membrane; dbSNP:rs121434304)"
FT /evidence="ECO:0000269|PubMed:17405131"
FT /id="VAR_069819"
FT VARIANT 522
FT /note="C -> Y (in CSNB1B; abolishes expression at the cell
FT membrane; dbSNP:rs62638208)"
FT /evidence="ECO:0000269|PubMed:17405131,
FT ECO:0000269|PubMed:23714322"
FT /id="VAR_069820"
FT VARIANT 712
FT /note="M -> V (in dbSNP:rs17078877)"
FT /id="VAR_055878"
FT VARIANT 781
FT /note="E -> K (in CSNB1B; abolishes expression at the cell
FT membrane; dbSNP:rs62638625)"
FT /evidence="ECO:0000269|PubMed:15781871,
FT ECO:0000269|PubMed:17405131"
FT /id="VAR_030757"
FT VARIANT 807
FT /note="A -> V (in dbSNP:rs17078874)"
FT /id="VAR_055879"
FT VARIANT 817
FT /note="T -> S (in dbSNP:rs17078857)"
FT /id="VAR_055880"
SQ SEQUENCE 877 AA; 95468 MW; 2AB27C5627B388C6 CRC64;
MARPRRAREP LLVALLPLAW LAQAGLARAA GSVRLAGGLT LGGLFPVHAR GAAGRACGQL
KKEQGVHRLE AMLYALDRVN ADPELLPGVR LGARLLDTCS RDTYALEQAL SFVQALIRGR
GDGDEVGVRC PGGVPPLRPA PPERVVAVVG ASASSVSIMV ANVLRLFAIP QISYASTAPE
LSDSTRYDFF SRVVPPDSYQ AQAMVDIVRA LGWNYVSTLA SEGNYGESGV EAFVQISREA
GGVCIAQSIK IPREPKPGEF SKVIRRLMET PNARGIIIFA NEDDIRRVLE AARQANLTGH
FLWVGSDSWG AKTSPILSLE DVAVGAITIL PKRASIDGFD QYFMTRSLEN NRRNIWFAEF
WEENFNCKLT SSGTQSDDST RKCTGEERIG RDSTYEQEGK VQFVIDAVYA IAHALHSMHQ
ALCPGHTGLC PAMEPTDGRM LLQYIRAVRF NGSAGTPVMF NENGDAPGRY DIFQYQATNG
SASSGGYQAV GQWAETLRLD VEALQWSGDP HEVPSSLCSL PCGPGERKKM VKGVPCCWHC
EACDGYRFQV DEFTCEACPG DMRPTPNHTG CRPTPVVRLS WSSPWAAPPL LLAVLGIVAT
TTVVATFVRY NNTPIVRASG RELSYVLLTG IFLIYAITFL MVAEPGAAVC AARRLFLGLG
TTLSYSALLT KTNRIYRIFE QGKRSVTPPP FISPTSQLVI TFSLTSLQVV GMIAWLGARP
PHSVIDYEEQ RTVDPEQARG VLKCDMSDLS LIGCLGYSLL LMVTCTVYAI KARGVPETFN
EAKPIGFTMY TTCIIWLAFV PIFFGTAQSA EKIYIQTTTL TVSLSLSASV SLGMLYVPKT
YVILFHPEQN VQKRKRSLKA TSTVAAPPKG EDAEAHK
