GRIA4_HUMAN
ID GRIA4_HUMAN Reviewed; 902 AA.
AC P48058; Q86XE8;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 16-DEC-2008, sequence version 2.
DT 03-AUG-2022, entry version 192.
DE RecName: Full=Glutamate receptor 4;
DE Short=GluR-4;
DE Short=GluR4;
DE AltName: Full=AMPA-selective glutamate receptor 4;
DE AltName: Full=GluR-D;
DE AltName: Full=Glutamate receptor ionotropic, AMPA 4;
DE Short=GluA4;
DE Flags: Precursor;
GN Name=GRIA4 {ECO:0000303|PubMed:29220673, ECO:0000312|HGNC:HGNC:4574};
GN Synonyms=GLUR4;
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] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=8589990;
RA Fletcher E.J., Nutt S.L., Hoo K.H., Elliott C.E., Korczak B.,
RA McWhinnie E.A., Kamboj R.K.;
RT "Cloning, expression and pharmacological characterization of a human
RT glutamate receptor: hGluR4.";
RL Recept. Channels 3:21-31(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION.
RX PubMed=21172611; DOI=10.1016/j.neuron.2010.11.026;
RA Kato A.S., Gill M.B., Ho M.T., Yu H., Tu Y., Siuda E.R., Wang H.,
RA Qian Y.W., Nisenbaum E.S., Tomita S., Bredt D.S.;
RT "Hippocampal AMPA receptor gating controlled by both TARP and cornichon
RT proteins.";
RL Neuron 68:1082-1096(2010).
RN [5]
RP INVOLVEMENT IN NEDSGA, AND VARIANTS NEDSGA SER-639; ASP-641; GLY-643;
RP VAL-644 AND PRO-697.
RX PubMed=29220673; DOI=10.1016/j.ajhg.2017.11.004;
RA Martin S., Chamberlin A., Shinde D.N., Hempel M., Strom T.M., Schreiber A.,
RA Johannsen J., Ousager L.B., Larsen M.J., Hansen L.K., Fatemi A.,
RA Cohen J.S., Lemke J., Soerensen K.P., Helbig K.L., Lessel D.,
RA Abou Jamra R.;
RT "De Novo Variants in GRIA4 Lead to Intellectual Disability with or without
RT Seizures and Gait Abnormalities.";
RL Am. J. Hum. Genet. 101:1013-1020(2017).
CC -!- FUNCTION: Receptor for glutamate that functions as ligand-gated ion
CC channel in the central nervous system and plays an important role in
CC excitatory synaptic transmission. L-glutamate acts as an excitatory
CC neurotransmitter at many synapses in the central nervous system.
CC Binding of the excitatory neurotransmitter L-glutamate induces a
CC conformation change, leading to the opening of the cation channel, and
CC thereby converts the chemical signal to an electrical impulse. The
CC receptor then desensitizes rapidly and enters a transient inactive
CC state, characterized by the presence of bound agonist. In the presence
CC of CACNG4 or CACNG7 or CACNG8, shows resensitization which is
CC characterized by a delayed accumulation of current flux upon continued
CC application of glutamate. {ECO:0000269|PubMed:21172611}.
CC -!- SUBUNIT: Homotetramer or heterotetramer of pore-forming glutamate
CC receptor subunits. Tetramers may be formed by the dimerization of
CC dimers. Interacts with EPB41L1 via its C-terminus (By similarity).
CC Found in a complex with GRIA1, GRIA2, GRIA3, CNIH2, CNIH3, CACNG2,
CC CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with CACNG5 and
CC PRKCG (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC P48058-2; Q8WTS1: ABHD5; NbExp=3; IntAct=EBI-17517256, EBI-2813554;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC Postsynaptic cell membrane; Multi-pass membrane protein. Cell
CC projection, dendrite. Note=Interaction with CNIH2, CNIH3 and PRKCG
CC promotes cell surface expression. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P48058-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P48058-2; Sequence=VSP_042742, VSP_042743;
CC -!- DOMAIN: The M4 transmembrane segment mediates tetramerization and is
CC required for cell surface expression. {ECO:0000250}.
CC -!- PTM: Palmitoylated. Depalmitoylated upon glutamate stimulation. Cys-611
CC palmitoylation leads to Golgi retention and decreased cell surface
CC expression. In contrast, Cys-837 palmitoylation does not affect cell
CC surface expression but regulates stimulation-dependent endocytosis (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Phosphorylated at Ser-862 by PRKCG; phosphorylation increases
CC plasma membrane-associated GRI4 expression. {ECO:0000250}.
CC -!- DISEASE: Neurodevelopmental disorder with or without seizures and gait
CC abnormalities (NEDSGA) [MIM:617864]: An autosomal dominant
CC neurodevelopmental disorder characterized by global developmental delay
CC apparent from infancy or early childhood, mild to profound intellectual
CC disability, hypertonia early in life, which progresses to spasticity
CC and impaired gait later, and behavioral abnormalities. Some patients
CC may develop seizures of variable severity early in life.
CC {ECO:0000269|PubMed:29220673}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: The postsynaptic actions of Glu are mediated by a
CC variety of receptors that are named according to their selective
CC agonists. This receptor binds AMPA (quisqualate) > glutamate > kainate.
CC -!- SIMILARITY: Belongs to the glutamate-gated ion channel (TC 1.A.10.1)
CC family. GRIA4 subfamily. {ECO:0000305}.
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DR EMBL; U16129; AAA95962.1; -; mRNA.
DR EMBL; AP000641; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000673; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000813; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP001561; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC045546; AAH45546.1; -; mRNA.
DR EMBL; BC142654; AAI42655.1; -; mRNA.
DR EMBL; BC150209; AAI50210.1; -; mRNA.
DR CCDS; CCDS41707.1; -. [P48058-2]
DR CCDS; CCDS8333.1; -. [P48058-1]
DR RefSeq; NP_000820.3; NM_000829.3. [P48058-1]
DR RefSeq; NP_001070711.2; NM_001077243.2.
DR RefSeq; NP_001070712.1; NM_001077244.1. [P48058-2]
DR RefSeq; NP_001106283.1; NM_001112812.1. [P48058-2]
DR RefSeq; XP_006718886.1; XM_006718823.1. [P48058-1]
DR AlphaFoldDB; P48058; -.
DR SMR; P48058; -.
DR BioGRID; 109150; 27.
DR IntAct; P48058; 3.
DR MINT; P48058; -.
DR STRING; 9606.ENSP00000282499; -.
DR BindingDB; P48058; -.
DR ChEMBL; CHEMBL3190; -.
DR DrugBank; DB00237; Butabarbital.
DR DrugBank; DB05047; CX-717.
DR DrugBank; DB00898; Ethanol.
DR DrugBank; DB13146; Fluciclovine (18F).
DR DrugBank; DB00142; Glutamic acid.
DR DrugBank; DB04982; Talampanel.
DR DrugCentral; P48058; -.
DR GuidetoPHARMACOLOGY; 447; -.
DR GlyGen; P48058; 6 sites.
DR iPTMnet; P48058; -.
DR PhosphoSitePlus; P48058; -.
DR BioMuta; GRIA4; -.
DR DMDM; 218512059; -.
DR EPD; P48058; -.
DR jPOST; P48058; -.
DR MassIVE; P48058; -.
DR PaxDb; P48058; -.
DR PeptideAtlas; P48058; -.
DR PRIDE; P48058; -.
DR ProteomicsDB; 55844; -. [P48058-1]
DR ProteomicsDB; 55845; -. [P48058-2]
DR Antibodypedia; 31872; 461 antibodies from 36 providers.
DR DNASU; 2893; -.
DR Ensembl; ENST00000282499.10; ENSP00000282499.5; ENSG00000152578.13. [P48058-1]
DR Ensembl; ENST00000393125.6; ENSP00000376833.2; ENSG00000152578.13. [P48058-2]
DR Ensembl; ENST00000428631.6; ENSP00000415551.2; ENSG00000152578.13. [P48058-2]
DR Ensembl; ENST00000530497.1; ENSP00000435775.1; ENSG00000152578.13. [P48058-1]
DR GeneID; 2893; -.
DR KEGG; hsa:2893; -.
DR MANE-Select; ENST00000282499.10; ENSP00000282499.5; NM_000829.4; NP_000820.4.
DR UCSC; uc001piu.2; human. [P48058-1]
DR CTD; 2893; -.
DR DisGeNET; 2893; -.
DR GeneCards; GRIA4; -.
DR HGNC; HGNC:4574; GRIA4.
DR HPA; ENSG00000152578; Group enriched (brain, retina).
DR MalaCards; GRIA4; -.
DR MIM; 138246; gene.
DR MIM; 617864; phenotype.
DR neXtProt; NX_P48058; -.
DR OpenTargets; ENSG00000152578; -.
DR Orphanet; 528084; Non-specific syndromic intellectual disability.
DR PharmGKB; PA28969; -.
DR VEuPathDB; HostDB:ENSG00000152578; -.
DR eggNOG; KOG1054; Eukaryota.
DR GeneTree; ENSGT00940000155677; -.
DR HOGENOM; CLU_633075_0_0_1; -.
DR InParanoid; P48058; -.
DR OMA; AMLVTWH; -.
DR OrthoDB; 188544at2759; -.
DR PhylomeDB; P48058; -.
DR TreeFam; TF315232; -.
DR PathwayCommons; P48058; -.
DR Reactome; R-HSA-399710; Activation of AMPA receptors.
DR Reactome; R-HSA-399719; Trafficking of AMPA receptors.
DR Reactome; R-HSA-416993; Trafficking of GluR2-containing AMPA receptors.
DR Reactome; R-HSA-438066; Unblocking of NMDA receptors, glutamate binding and activation.
DR Reactome; R-HSA-8849932; Synaptic adhesion-like molecules.
DR SignaLink; P48058; -.
DR SIGNOR; P48058; -.
DR BioGRID-ORCS; 2893; 6 hits in 1070 CRISPR screens.
DR ChiTaRS; GRIA4; human.
DR GeneWiki; GRIA4; -.
DR GenomeRNAi; 2893; -.
DR Pharos; P48058; Tclin.
DR PRO; PR:P48058; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P48058; protein.
DR Bgee; ENSG00000152578; Expressed in cerebellar hemisphere and 122 other tissues.
DR ExpressionAtlas; P48058; baseline and differential.
DR Genevisible; P48058; HS.
DR GO; GO:0032281; C:AMPA glutamate receptor complex; ISS:UniProtKB.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0043197; C:dendritic spine; ISS:ARUK-UCL.
DR GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome.
DR GO; GO:1903561; C:extracellular vesicle; HDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; ISS:ARUK-UCL.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0045211; C:postsynaptic membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0004971; F:AMPA glutamate receptor activity; IDA:UniProtKB.
DR GO; GO:0001540; F:amyloid-beta binding; NAS:ARUK-UCL.
DR GO; GO:0004970; F:ionotropic glutamate receptor activity; ISS:UniProtKB.
DR GO; GO:0015276; F:ligand-gated ion channel activity; IBA:GO_Central.
DR GO; GO:0038023; F:signaling receptor activity; IBA:GO_Central.
DR GO; GO:0007215; P:glutamate receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0034392; P:negative regulation of smooth muscle cell apoptotic process; IGI:ARUK-UCL.
DR InterPro; IPR001828; ANF_lig-bd_rcpt.
DR InterPro; IPR019594; Glu/Gly-bd.
DR InterPro; IPR001508; Iono_rcpt_met.
DR InterPro; IPR001320; Iontro_rcpt.
DR InterPro; IPR028082; Peripla_BP_I.
DR Pfam; PF01094; ANF_receptor; 1.
DR Pfam; PF00060; Lig_chan; 1.
DR Pfam; PF10613; Lig_chan-Glu_bd; 1.
DR PRINTS; PR00177; NMDARECEPTOR.
DR SMART; SM00918; Lig_chan-Glu_bd; 1.
DR SMART; SM00079; PBPe; 1.
DR SUPFAM; SSF53822; SSF53822; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Cell projection; Disease variant;
KW Disulfide bond; Glycoprotein; Intellectual disability; Ion channel;
KW Ion transport; Ligand-gated ion channel; Lipoprotein; Membrane; Palmitate;
KW Phosphoprotein; Postsynaptic cell membrane; Receptor; Reference proteome;
KW Signal; Synapse; Transmembrane; Transmembrane helix; Transport.
FT SIGNAL 1..20
FT /evidence="ECO:0000255"
FT CHAIN 21..902
FT /note="Glutamate receptor 4"
FT /id="PRO_0000011538"
FT TOPO_DOM 22..544
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 545..565
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TOPO_DOM 566..592
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT INTRAMEM 593..608
FT /note="Helical; Pore-forming"
FT /evidence="ECO:0000250"
FT INTRAMEM 609..611
FT /evidence="ECO:0000250"
FT TOPO_DOM 612..617
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 618..638
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TOPO_DOM 639..813
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 814..834
FT /note="Helical; Name=M4"
FT /evidence="ECO:0000250"
FT TOPO_DOM 835..902
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT BINDING 472
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250"
FT BINDING 500..502
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250"
FT BINDING 507
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250"
FT BINDING 676..677
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250"
FT BINDING 727
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250"
FT MOD_RES 862
FT /note="Phosphoserine; by PKC/PRKCG"
FT /evidence="ECO:0000250|UniProtKB:P19493"
FT LIPID 611
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT LIPID 837
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT CARBOHYD 52
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 56
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 258
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 371
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 407
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 414
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 84..331
FT /evidence="ECO:0000250"
FT DISULFID 740..795
FT /evidence="ECO:0000250"
FT VAR_SEQ 424..433
FT /note="ESPYVMYKKN -> PLMKNPILRN (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_042742"
FT VAR_SEQ 434..902
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_042743"
FT VARIANT 639
FT /note="T -> S (in NEDSGA; dbSNP:rs1555050158)"
FT /evidence="ECO:0000269|PubMed:29220673"
FT /id="VAR_080751"
FT VARIANT 641
FT /note="N -> D (in NEDSGA; dbSNP:rs1555050165)"
FT /evidence="ECO:0000269|PubMed:29220673"
FT /id="VAR_080752"
FT VARIANT 643
FT /note="A -> G (in NEDSGA; dbSNP:rs1555050171)"
FT /evidence="ECO:0000269|PubMed:29220673"
FT /id="VAR_080753"
FT VARIANT 644
FT /note="A -> V (in NEDSGA; dbSNP:rs1555050174)"
FT /evidence="ECO:0000269|PubMed:29220673"
FT /id="VAR_080754"
FT VARIANT 697
FT /note="R -> P (in NEDSGA; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:29220673"
FT /id="VAR_080755"
FT CONFLICT 54
FT /note="S -> A (in Ref. 1; AAA95962)"
FT /evidence="ECO:0000305"
FT CONFLICT 273
FT /note="I -> T (in Ref. 1; AAA95962)"
FT /evidence="ECO:0000305"
FT CONFLICT 327..328
FT /note="NA -> KS (in Ref. 1; AAA95962)"
FT /evidence="ECO:0000305"
FT CONFLICT 732..733
FT /note="EY -> DN (in Ref. 1; AAA95962)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 902 AA; 100871 MW; 7793AEF0AB829FC5 CRC64;
MRIISRQIVL LFSGFWGLAM GAFPSSVQIG GLFIRNTDQE YTAFRLAIFL HNTSPNASEA
PFNLVPHVDN IETANSFAVT NAFCSQYSRG VFAIFGLYDK RSVHTLTSFC SALHISLITP
SFPTEGESQF VLQLRPSLRG ALLSLLDHYE WNCFVFLYDT DRGYSILQAI MEKAGQNGWH
VSAICVENFN DVSYRQLLEE LDRRQEKKFV IDCEIERLQN ILEQIVSVGK HVKGYHYIIA
NLGFKDISLE RFIHGGANVT GFQLVDFNTP MVIKLMDRWK KLDQREYPGS ETPPKYTSAL
TYDGVLVMAE TFRSLRRQKI DISRRGNAGD CLANPAAPWG QGIDMERTLK QVRIQGLTGN
VQFDHYGRRV NYTMDVFELK STGPRKVGYW NDMDKLVLIQ DVPTLGNDTA AIENRTVVVT
TIMESPYVMY KKNHEMFEGN DKYEGYCVDL ASEIAKHIGI KYKIAIVPDG KYGARDADTK
IWNGMVGELV YGKAEIAIAP LTITLVREEV IDFSKPFMSL GISIMIKKPQ KSKPGVFSFL
DPLAYEIWMC IVFAYIGVSV VLFLVSRFSP YEWHTEEPED GKEGPSDQPP NEFGIFNSLW
FSLGAFMQQG CDISPRSLSG RIVGGVWWFF TLIIISSYTA NLAAFLTVER MVSPIESAED
LAKQTEIAYG TLDSGSTKEF FRRSKIAVYE KMWTYMRSAE PSVFTRTTAE GVARVRKSKG
KFAFLLESTM NEYIEQRKPC DTMKVGGNLD SKGYGVATPK GSSLRTPVNL AVLKLSEAGV
LDKLKNKWWY DKGECGPKDS GSKDKTSALS LSNVAGVFYI LVGGLGLAML VALIEFCYKS
RAEAKRMKLT FSEAIRNKAR LSITGSVGEN GRVLTPDCPK AVHTGTAIRQ SSGLAVIASD
LP
