Full text data of GRIN1
GRIN1
(NMDAR1)
[Confidence: low (only semi-automatic identification from reviews)]
Glutamate receptor ionotropic, NMDA 1; GluN1 (Glutamate [NMDA] receptor subunit zeta-1; N-methyl-D-aspartate receptor subunit NR1; NMD-R1; Flags: Precursor)
Glutamate receptor ionotropic, NMDA 1; GluN1 (Glutamate [NMDA] receptor subunit zeta-1; N-methyl-D-aspartate receptor subunit NR1; NMD-R1; Flags: Precursor)
UniProt
Q05586
ID NMDZ1_HUMAN Reviewed; 938 AA.
AC Q05586; A6NLK7; A6NLR1; C9K0X1; P35437; Q12867; Q12868; Q5VSF3;
read moreAC Q5VSF4; Q5VSF5; Q5VSF6; Q5VSF7; Q5VSF8; Q9UPF8; Q9UPF9;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 1.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Glutamate receptor ionotropic, NMDA 1;
DE Short=GluN1;
DE AltName: Full=Glutamate [NMDA] receptor subunit zeta-1;
DE AltName: Full=N-methyl-D-aspartate receptor subunit NR1;
DE Short=NMD-R1;
DE Flags: Precursor;
GN Name=GRIN1; Synonyms=NMDAR1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [MRNA] OF
RP 11-938 (ISOFORM 3), AND NUCLEOTIDE SEQUENCE [MRNA] OF 300-938 (ISOFORM
RP 2).
RC TISSUE=Brain;
RX PubMed=8406025; DOI=10.1016/0378-1119(93)90309-Q;
RA Foldes R.L., Rampersad V., Kamboj R.K.;
RT "Cloning and sequence analysis of cDNAs encoding human hippocampus N-
RT methyl-D-aspartate receptor subunits: evidence for alternative RNA
RT splicing.";
RL Gene 131:293-298(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=7679115;
RA Karp S.J., Masu M., Eki T., Ozawa K., Nakanishi S.;
RT "Molecular cloning and chromosomal localization of the key subunit of
RT the human N-methyl-D-aspartate receptor.";
RL J. Biol. Chem. 268:3728-3733(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=7685113; DOI=10.1073/pnas.90.11.5057;
RA Planells-Cases R., Sun W., Ferrer-Montiel A.V., Montal M.;
RT "Molecular cloning, functional expression, and pharmacological
RT characterization of an N-methyl-D-aspartate receptor subunit from
RT human brain.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:5057-5061(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7622053; DOI=10.1016/0378-1119(95)00044-7;
RA Zimmer M., Fink T.M., Franke Y., Lichter P., Spiess J.;
RT "Cloning and structure of the gene encoding the human N-methyl-D-
RT aspartate receptor (NMDAR1).";
RL Gene 159:219-223(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 6 AND 7), AND VARIANTS MET-540
RP AND SER-682.
RX PubMed=9231706;
RA Nash N.R., Heilman C.J., Rees H.D., Levey A.I.;
RT "Cloning and localization of exon 5-containing isoforms of the NMDAR1
RT subunit in human and rat brains.";
RL J. Neurochem. 69:485-493(1997).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 332-922 (ISOFORM 4), AND NUCLEOTIDE
RP SEQUENCE [MRNA] OF 86-259 (ISOFORM 5).
RC TISSUE=Cerebellum, and Hippocampus;
RX PubMed=7926821; DOI=10.1016/0378-1119(94)90089-2;
RA Foldes R.L., Rampersad V., Kamboj R.K.;
RT "Cloning and sequence analysis of additional splice variants encoding
RT human N-methyl-D-aspartate receptor (hNR1) subunits.";
RL Gene 147:303-304(1994).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 364-464 (ISOFORMS 1/2/3).
RX PubMed=7681588; DOI=10.1073/pnas.90.6.2174;
RA Younkin D.P., Tang C.-M., Hardy M., Reddy U.R., Shi Q.-Y.,
RA Pleasure S.J., Lee V.M.-Y., Pleasure D.;
RT "Inducible expression of neuronal glutamate receptor channels in the
RT NT2 human cell line.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:2174-2178(1993).
RN [9]
RP PHOSPHORYLATION BY PKC.
RX PubMed=8316301; DOI=10.1038/364070a0;
RA Tingley W.G., Roche K.W., Thompson A.K., Huganir R.L.;
RT "Regulation of NMDA receptor phosphorylation by alternative splicing
RT of the C-terminal domain.";
RL Nature 364:70-73(1993).
RN [10]
RP INTERCHAIN DISULFIDE BOND.
RX PubMed=14732708; DOI=10.1074/jbc.M313446200;
RA Papadakis M., Hawkins L.M., Stephenson F.A.;
RT "Appropriate NR1-NR1 disulfide-linked homodimer formation is requisite
RT for efficient expression of functional, cell surface N-methyl-D-
RT aspartate NR1/NR2 receptors.";
RL J. Biol. Chem. 279:14703-14712(2004).
RN [11]
RP INTERACTION WITH MYZAP.
RX PubMed=18849881; DOI=10.1097/WNR.0b013e328317f05f;
RA Roginski R.S., Goubaeva F., Mikami M., Fried-Cassorla E., Nair M.R.,
RA Yang J.;
RT "GRINL1A colocalizes with N-methyl D-aspartate receptor NR1 subunit
RT and reduces N-methyl D-aspartate toxicity.";
RL NeuroReport 19:1721-1726(2008).
RN [12]
RP STRUCTURE BY NMR OF 599-621.
RX PubMed=10201407; DOI=10.1038/7610;
RA Opella S.J., Marassi F.M., Gesell J.J., Valente A.P., Kim Y.,
RA Oblatt-Montal M., Montal M.;
RT "Structures of the M2 channel-lining segments from nicotinic
RT acetylcholine and NMDA receptors by NMR spectroscopy.";
RL Nat. Struct. Biol. 6:374-379(1999).
RN [13]
RP VARIANTS MRD8 SER-560 INS AND LYS-662, AND CHARACTERIZATION OF
RP VARIANTS MRD8 SER-560 INS AND LYS-662.
RX PubMed=21376300; DOI=10.1016/j.ajhg.2011.02.001;
RA Hamdan F.F., Gauthier J., Araki Y., Lin D.T., Yoshizawa Y.,
RA Higashi K., Park A.R., Spiegelman D., Dobrzeniecka S., Piton A.,
RA Tomitori H., Daoud H., Massicotte C., Henrion E., Diallo O.,
RA Shekarabi M., Marineau C., Shevell M., Maranda B., Mitchell G.,
RA Nadeau A., D'Anjou G., Vanasse M., Srour M., Lafreniere R.G.,
RA Drapeau P., Lacaille J.C., Kim E., Lee J.R., Igarashi K.,
RA Huganir R.L., Rouleau G.A., Michaud J.L.;
RT "Excess of de novo deleterious mutations in genes associated with
RT glutamatergic systems in nonsyndromic intellectual disability.";
RL Am. J. Hum. Genet. 88:306-316(2011).
CC -!- FUNCTION: NMDA receptor subtype of glutamate-gated ion channels
CC with high calcium permeability and voltage-dependent sensitivity
CC to magnesium. Mediated by glycine. This protein plays a key role
CC in synaptic plasticity, synaptogenesis, excitotoxicity, memory
CC acquisition and learning. It mediates neuronal functions in
CC glutamate neurotransmission. Is involved in the cell surface
CC targeting of NMDA receptors (By similarity).
CC -!- SUBUNIT: Forms heteromeric channel of a zeta subunit (GRIN1), a
CC epsilon subunit (GRIN2A, GRIN2B, GRIN2C or GRIN2D) and a third
CC subunit (GRIN3A or GRIN3B); disulfide-linked. Found in a complex
CC with GRIN2A or GRIN2B, GRIN3A or GRIN3B and PPP2CB. Interacts with
CC DLG4 and MPDZ. Interacts with SNX27 (via PDZ domain); the
CC interaction is required for recycling to the plasma membrane when
CC endocytosed and prevent degradation in lysosomes (By similarity).
CC Interacts with LRFN1 and LRFN2 (By similarity). Interacts with
CC MYZAP.
CC -!- INTERACTION:
CC Q62936:Dlg3 (xeno); NbExp=3; IntAct=EBI-8286218, EBI-349596;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein
CC (By similarity). Cell junction, synapse, postsynaptic cell
CC membrane (By similarity). Cell junction, synapse, postsynaptic
CC cell membrane, postsynaptic density (By similarity). Note=Enriched
CC in postsynaptic plasma membrane and postsynaptic densities (By
CC similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=3; Synonyms=Long, NR1-3;
CC IsoId=Q05586-1; Sequence=Displayed;
CC Name=1; Synonyms=Short, NR1-1;
CC IsoId=Q05586-2; Sequence=VSP_000137, VSP_000138;
CC Name=2; Synonyms=Medium, NR1-2;
CC IsoId=Q05586-3; Sequence=VSP_000139;
CC Name=4;
CC IsoId=Q05586-4; Sequence=VSP_011778, VSP_011779;
CC Name=5;
CC IsoId=Q05586-5; Sequence=VSP_011777;
CC Name=6;
CC IsoId=Q05586-6; Sequence=VSP_011777, VSP_011778, VSP_011779;
CC Name=7;
CC IsoId=Q05586-7; Sequence=VSP_011777, VSP_045464;
CC -!- PTM: NMDA is probably regulated by C-terminal phosphorylation of
CC an isoform of NR1 by PKC. Dephosphorylated on Ser-897 probably by
CC protein phosphatase 2A (PPP2CB). Its phosphorylated state is
CC influenced by the formation of the NMDAR-PPP2CB complex and the
CC NMDAR channel activity.
CC -!- DISEASE: Mental retardation, autosomal dominant 8 (MRD8)
CC [MIM:614254]: A disorder characterized by significantly below
CC average general intellectual functioning associated with
CC impairments in adaptive behavior and manifested during the
CC developmental period. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the glutamate-gated ion channel
CC (TC 1.A.10.1) family. NR1/GRIN1 subfamily.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=NMDA receptor entry;
CC URL="http://en.wikipedia.org/wiki/NMDA_receptor";
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DR EMBL; L13266; AAB59360.1; -; mRNA.
DR EMBL; L13267; AAA36198.1; -; mRNA.
DR EMBL; L13268; AAB59361.1; -; mRNA.
DR EMBL; D13515; BAA02732.1; -; mRNA.
DR EMBL; L05666; AAA21180.1; -; mRNA.
DR EMBL; AF015730; AAB67723.1; -; mRNA.
DR EMBL; AF015731; AAB67724.1; -; mRNA.
DR EMBL; Z32772; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; Z32773; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; Z32774; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL929554; CAH72874.2; -; Genomic_DNA.
DR EMBL; AL929554; CAH72875.2; -; Genomic_DNA.
DR EMBL; AL929554; CAH72876.2; -; Genomic_DNA.
DR EMBL; AL929554; CAH72879.2; -; Genomic_DNA.
DR EMBL; U08106; AAA62111.1; -; mRNA.
DR EMBL; U08107; AAA62112.1; -; mRNA.
DR EMBL; S57708; AAB25917.1; -; mRNA.
DR PIR; A46612; A46612.
DR PIR; A47551; A47551.
DR RefSeq; NP_000823.4; NM_000832.6.
DR RefSeq; NP_001172019.1; NM_001185090.1.
DR RefSeq; NP_001172020.1; NM_001185091.1.
DR RefSeq; NP_015566.1; NM_007327.3.
DR RefSeq; NP_067544.1; NM_021569.3.
DR RefSeq; XP_005266128.1; XM_005266071.1.
DR RefSeq; XP_005266130.1; XM_005266073.1.
DR UniGene; Hs.558334; -.
DR PDB; 2HQW; X-ray; 1.90 A; B=875-898.
DR PDB; 2NR1; NMR; -; A=599-621.
DR PDB; 3BYA; X-ray; 1.85 A; B=875-898.
DR PDBsum; 2HQW; -.
DR PDBsum; 2NR1; -.
DR PDBsum; 3BYA; -.
DR ProteinModelPortal; Q05586; -.
DR SMR; Q05586; 24-838.
DR IntAct; Q05586; 7.
DR MINT; MINT-1900224; -.
DR BindingDB; Q05586; -.
DR ChEMBL; CHEMBL2015; -.
DR DrugBank; DB00142; L-Glutamic Acid.
DR DrugBank; DB01173; Orphenadrine.
DR GuidetoPHARMACOLOGY; 455; -.
DR TCDB; 1.A.10.1.6; the glutamate-gated ion channel (gic) family of neurotransmitter receptors.
DR PhosphoSite; Q05586; -.
DR DMDM; 548377; -.
DR PaxDb; Q05586; -.
DR PRIDE; Q05586; -.
DR Ensembl; ENST00000315048; ENSP00000316696; ENSG00000176884.
DR Ensembl; ENST00000371546; ENSP00000360601; ENSG00000176884.
DR Ensembl; ENST00000371550; ENSP00000360605; ENSG00000176884.
DR Ensembl; ENST00000371553; ENSP00000360608; ENSG00000176884.
DR Ensembl; ENST00000371559; ENSP00000360614; ENSG00000176884.
DR Ensembl; ENST00000371560; ENSP00000360615; ENSG00000176884.
DR Ensembl; ENST00000371561; ENSP00000360616; ENSG00000176884.
DR GeneID; 2902; -.
DR KEGG; hsa:2902; -.
DR UCSC; uc004clk.3; human.
DR CTD; 2902; -.
DR GeneCards; GC09P140032; -.
DR HGNC; HGNC:4584; GRIN1.
DR HPA; CAB006831; -.
DR MIM; 138249; gene.
DR MIM; 614254; phenotype.
DR neXtProt; NX_Q05586; -.
DR Orphanet; 178469; Autosomal dominant nonsyndromic intellectual deficit.
DR PharmGKB; PA28978; -.
DR eggNOG; NOG282132; -.
DR HOVERGEN; HBG052638; -.
DR KO; K05208; -.
DR OMA; WNHVILL; -.
DR OrthoDB; EOG79GT5V; -.
DR PhylomeDB; Q05586; -.
DR Reactome; REACT_13685; Neuronal System.
DR SignaLink; Q05586; -.
DR ChiTaRS; GRIN1; human.
DR EvolutionaryTrace; Q05586; -.
DR GeneWiki; GRIN1; -.
DR GenomeRNAi; 2902; -.
DR NextBio; 11487; -.
DR PMAP-CutDB; Q5VSF3; -.
DR PRO; PR:Q05586; -.
DR ArrayExpress; Q05586; -.
DR Bgee; Q05586; -.
DR CleanEx; HS_GRIN1; -.
DR Genevestigator; Q05586; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0009986; C:cell surface; ISS:BHF-UCL.
DR GO; GO:0032590; C:dendrite membrane; IEA:Ensembl.
DR GO; GO:0043197; C:dendritic spine; ISS:BHF-UCL.
DR GO; GO:0060076; C:excitatory synapse; ISS:BHF-UCL.
DR GO; GO:0017146; C:N-methyl-D-aspartate selective glutamate receptor complex; IDA:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB.
DR GO; GO:0045211; C:postsynaptic membrane; ISS:UniProtKB.
DR GO; GO:0043083; C:synaptic cleft; ISS:BHF-UCL.
DR GO; GO:0008021; C:synaptic vesicle; ISS:UniProtKB.
DR GO; GO:0043195; C:terminal bouton; ISS:BHF-UCL.
DR GO; GO:0005262; F:calcium channel activity; IEA:Ensembl.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0005516; F:calmodulin binding; ISS:UniProtKB.
DR GO; GO:0005234; F:extracellular-glutamate-gated ion channel activity; IEA:InterPro.
DR GO; GO:0016595; F:glutamate binding; IDA:UniProtKB.
DR GO; GO:0016594; F:glycine binding; IDA:UniProtKB.
DR GO; GO:0004972; F:N-methyl-D-aspartate selective glutamate receptor activity; IEA:Ensembl.
DR GO; GO:0042165; F:neurotransmitter binding; ISS:BHF-UCL.
DR GO; GO:0022843; F:voltage-gated cation channel activity; IEA:Ensembl.
DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl.
DR GO; GO:0055074; P:calcium ion homeostasis; ISS:UniProtKB.
DR GO; GO:0006812; P:cation transport; IDA:UniProtKB.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0071287; P:cellular response to manganese ion; IEA:Ensembl.
DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR GO; GO:0001661; P:conditioned taste aversion; IEA:Ensembl.
DR GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0007616; P:long-term memory; IEA:Ensembl.
DR GO; GO:0060179; P:male mating behavior; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0008355; P:olfactory learning; IEA:Ensembl.
DR GO; GO:0021586; P:pons maturation; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:2000463; P:positive regulation of excitatory postsynaptic membrane potential; ISS:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; ISS:UniProtKB.
DR GO; GO:0060134; P:prepulse inhibition; IEA:Ensembl.
DR GO; GO:0018964; P:propylene metabolic process; ISS:BHF-UCL.
DR GO; GO:0050770; P:regulation of axonogenesis; IEA:Ensembl.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; IEA:Ensembl.
DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl.
DR GO; GO:0043576; P:regulation of respiratory gaseous exchange; IEA:Ensembl.
DR GO; GO:0051963; P:regulation of synapse assembly; IEA:Ensembl.
DR GO; GO:0007585; P:respiratory gaseous exchange; IEA:Ensembl.
DR GO; GO:0001975; P:response to amphetamine; IEA:Ensembl.
DR GO; GO:0051592; P:response to calcium ion; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IDA:UniProtKB.
DR GO; GO:0060992; P:response to fungicide; IEA:Ensembl.
DR GO; GO:0043278; P:response to morphine; IEA:Ensembl.
DR GO; GO:0048511; P:rhythmic process; IEA:Ensembl.
DR GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl.
DR GO; GO:0035176; P:social behavior; IEA:Ensembl.
DR GO; GO:0001967; P:suckling behavior; IEA:Ensembl.
DR GO; GO:0035249; P:synaptic transmission, glutamatergic; IEA:Ensembl.
DR GO; GO:0008542; P:visual learning; ISS:UniProtKB.
DR InterPro; IPR001828; ANF_lig-bd_rcpt.
DR InterPro; IPR018882; CaM-bd_C0_NMDA_rcpt_NR1.
DR InterPro; IPR019594; Glu_rcpt_Glu/Gly-bd.
DR InterPro; IPR001320; Iontro_glu_rcpt.
DR InterPro; IPR001508; NMDA_rcpt.
DR InterPro; IPR028082; Peripla_BP_I.
DR InterPro; IPR001638; SBP_bac_3.
DR Pfam; PF01094; ANF_receptor; 1.
DR Pfam; PF10562; CaM_bdg_C0; 1.
DR Pfam; PF00060; Lig_chan; 1.
DR Pfam; PF00497; SBP_bac_3; 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 3D-structure; Alternative splicing; Calcium; Cell junction;
KW Cell membrane; Complete proteome; Disease mutation; Disulfide bond;
KW Glycoprotein; Ion channel; Ion transport; Ligand-gated ion channel;
KW Magnesium; Membrane; Mental retardation; Phosphoprotein; Polymorphism;
KW Postsynaptic cell membrane; Receptor; Reference proteome; Signal;
KW Synapse; Transmembrane; Transmembrane helix; Transport.
FT SIGNAL 1 18 Potential.
FT CHAIN 19 938 Glutamate receptor ionotropic, NMDA 1.
FT /FTId=PRO_0000011587.
FT TOPO_DOM 19 559 Extracellular (Potential).
FT TRANSMEM 560 580 Helical; (Potential).
FT TOPO_DOM 581 636 Cytoplasmic (Potential).
FT TRANSMEM 637 657 Helical; (Potential).
FT TOPO_DOM 658 812 Extracellular (Potential).
FT TRANSMEM 813 833 Helical; (Potential).
FT TOPO_DOM 834 938 Cytoplasmic (Potential).
FT REGION 516 518 Glycine binding (By similarity).
FT BINDING 523 523 Glycine (By similarity).
FT BINDING 688 688 Glycine (By similarity).
FT BINDING 732 732 Glycine (By similarity).
FT MOD_RES 889 889 Phosphoserine; by PKC (Probable).
FT MOD_RES 890 890 Phosphoserine; by PKC (Probable).
FT MOD_RES 896 896 Phosphoserine; by PKC (Probable).
FT MOD_RES 897 897 Phosphoserine; by PKC (Probable).
FT CARBOHYD 61 61 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 203 203 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 239 239 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 276 276 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 300 300 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 350 350 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 368 368 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 440 440 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 471 471 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 491 491 N-linked (GlcNAc...) (Potential).
FT DISULFID 79 79 Interchain.
FT VAR_SEQ 190 190 K -> KSKKRNYENLDQLSYDNKRGPK (in isoform
FT 5, isoform 6 and isoform 7).
FT /FTId=VSP_011777.
FT VAR_SEQ 864 938 DRKSGRAEPDPKKKATFRAITSTLASSFKRRRSSKDTSTGG
FT GRGALQNQKDTVLPRRAIEREEGQLQLCSRHRES -> QYH
FT PTDITGPLNLSDPSVSTVV (in isoform 7).
FT /FTId=VSP_045464.
FT VAR_SEQ 864 900 Missing (in isoform 2).
FT /FTId=VSP_000139.
FT VAR_SEQ 864 885 DRKSGRAEPDPKKKATFRAITS -> QYHPTDITGPLNLSD
FT PSVSTVV (in isoform 1).
FT /FTId=VSP_000137.
FT VAR_SEQ 886 938 Missing (in isoform 1).
FT /FTId=VSP_000138.
FT VAR_SEQ 901 922 STGGGRGALQNQKDTVLPRRAI -> QYHPTDITGPLNLSD
FT PSVSTVV (in isoform 4 and isoform 6).
FT /FTId=VSP_011778.
FT VAR_SEQ 923 938 Missing (in isoform 4 and isoform 6).
FT /FTId=VSP_011779.
FT VARIANT 540 540 I -> M (in dbSNP:rs3181457).
FT /FTId=VAR_049187.
FT VARIANT 560 560 S -> SS (in MRD8; there is near abolition
FT of the activity of the NMDA receptor in
FT Xenopus oocytes; alters the 3-dimensional
FT structure at the receptor's channel pore
FT entrance).
FT /FTId=VAR_066597.
FT VARIANT 662 662 E -> K (in MRD8; this mutation produces a
FT significant increase in NMDA receptor-
FT induced calcium currents; excessive
FT calcium influx through NMDA receptor
FT could lead to excitotoxic neuronal cell
FT damage).
FT /FTId=VAR_066598.
FT VARIANT 682 682 A -> S (in dbSNP:rs1126448).
FT /FTId=VAR_069057.
FT CONFLICT 389 389 P -> S (in Ref. 8; AAB25917).
FT CONFLICT 488 488 E -> K (in Ref. 1; AAB59361).
FT HELIX 600 620
FT HELIX 877 892
SQ SEQUENCE 938 AA; 105373 MW; CDF5402769E530AB CRC64;
MSTMRLLTLA LLFSCSVARA ACDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL
NATSVTHKPN AIQMALSVCE DLISSQVYAI LVSHPPTPND HFTPTPVSYT AGFYRIPVLG
LTTRMSIYSD KSIHLSFLRT VPPYSHQSSV WFEMMRVYSW NHIILLVSDD HEGRAAQKRL
ETLLEERESK AEKVLQFDPG TKNVTALLME AKELEARVII LSASEDDAAT VYRAAAMLNM
TGSGYVWLVG EREISGNALR YAPDGILGLQ LINGKNESAH ISDAVGVVAQ AVHELLEKEN
ITDPPRGCVG NTNIWKTGPL FKRVLMSSKY ADGVTGRVEF NEDGDRKFAN YSIMNLQNRK
LVQVGIYNGT HVIPNDRKII WPGGETEKPR GYQMSTRLKI VTIHQEPFVY VKPTLSDGTC
KEEFTVNGDP VKKVICTGPN DTSPGSPRHT VPQCCYGFCI DLLIKLARTM NFTYEVHLVA
DGKFGTQERV NNSNKKEWNG MMGELLSGQA DMIVAPLTIN NERAQYIEFS KPFKYQGLTI
LVKKEIPRST LDSFMQPFQS TLWLLVGLSV HVVAVMLYLL DRFSPFGRFK VNSEEEEEDA
LTLSSAMWFS WGVLLNSGIG EGAPRSFSAR ILGMVWAGFA MIIVASYTAN LAAFLVLDRP
EERITGINDP RLRNPSDKFI YATVKQSSVD IYFRRQVELS TMYRHMEKHN YESAAEAIQA
VRDNKLHAFI WDSAVLEFEA SQKCDLVTTG ELFFRSGFGI GMRKDSPWKQ NVSLSILKSH
ENGFMEDLDK TWVRYQECDS RSNAPATLTF ENMAGVFMLV AGGIVAGIFL IFIEIAYKRH
KDARRKQMQL AFAAVNVWRK NLQDRKSGRA EPDPKKKATF RAITSTLASS FKRRRSSKDT
STGGGRGALQ NQKDTVLPRR AIEREEGQLQ LCSRHRES
//
ID NMDZ1_HUMAN Reviewed; 938 AA.
AC Q05586; A6NLK7; A6NLR1; C9K0X1; P35437; Q12867; Q12868; Q5VSF3;
read moreAC Q5VSF4; Q5VSF5; Q5VSF6; Q5VSF7; Q5VSF8; Q9UPF8; Q9UPF9;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 1.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Glutamate receptor ionotropic, NMDA 1;
DE Short=GluN1;
DE AltName: Full=Glutamate [NMDA] receptor subunit zeta-1;
DE AltName: Full=N-methyl-D-aspartate receptor subunit NR1;
DE Short=NMD-R1;
DE Flags: Precursor;
GN Name=GRIN1; Synonyms=NMDAR1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [MRNA] OF
RP 11-938 (ISOFORM 3), AND NUCLEOTIDE SEQUENCE [MRNA] OF 300-938 (ISOFORM
RP 2).
RC TISSUE=Brain;
RX PubMed=8406025; DOI=10.1016/0378-1119(93)90309-Q;
RA Foldes R.L., Rampersad V., Kamboj R.K.;
RT "Cloning and sequence analysis of cDNAs encoding human hippocampus N-
RT methyl-D-aspartate receptor subunits: evidence for alternative RNA
RT splicing.";
RL Gene 131:293-298(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=7679115;
RA Karp S.J., Masu M., Eki T., Ozawa K., Nakanishi S.;
RT "Molecular cloning and chromosomal localization of the key subunit of
RT the human N-methyl-D-aspartate receptor.";
RL J. Biol. Chem. 268:3728-3733(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=7685113; DOI=10.1073/pnas.90.11.5057;
RA Planells-Cases R., Sun W., Ferrer-Montiel A.V., Montal M.;
RT "Molecular cloning, functional expression, and pharmacological
RT characterization of an N-methyl-D-aspartate receptor subunit from
RT human brain.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:5057-5061(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7622053; DOI=10.1016/0378-1119(95)00044-7;
RA Zimmer M., Fink T.M., Franke Y., Lichter P., Spiess J.;
RT "Cloning and structure of the gene encoding the human N-methyl-D-
RT aspartate receptor (NMDAR1).";
RL Gene 159:219-223(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 6 AND 7), AND VARIANTS MET-540
RP AND SER-682.
RX PubMed=9231706;
RA Nash N.R., Heilman C.J., Rees H.D., Levey A.I.;
RT "Cloning and localization of exon 5-containing isoforms of the NMDAR1
RT subunit in human and rat brains.";
RL J. Neurochem. 69:485-493(1997).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 332-922 (ISOFORM 4), AND NUCLEOTIDE
RP SEQUENCE [MRNA] OF 86-259 (ISOFORM 5).
RC TISSUE=Cerebellum, and Hippocampus;
RX PubMed=7926821; DOI=10.1016/0378-1119(94)90089-2;
RA Foldes R.L., Rampersad V., Kamboj R.K.;
RT "Cloning and sequence analysis of additional splice variants encoding
RT human N-methyl-D-aspartate receptor (hNR1) subunits.";
RL Gene 147:303-304(1994).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 364-464 (ISOFORMS 1/2/3).
RX PubMed=7681588; DOI=10.1073/pnas.90.6.2174;
RA Younkin D.P., Tang C.-M., Hardy M., Reddy U.R., Shi Q.-Y.,
RA Pleasure S.J., Lee V.M.-Y., Pleasure D.;
RT "Inducible expression of neuronal glutamate receptor channels in the
RT NT2 human cell line.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:2174-2178(1993).
RN [9]
RP PHOSPHORYLATION BY PKC.
RX PubMed=8316301; DOI=10.1038/364070a0;
RA Tingley W.G., Roche K.W., Thompson A.K., Huganir R.L.;
RT "Regulation of NMDA receptor phosphorylation by alternative splicing
RT of the C-terminal domain.";
RL Nature 364:70-73(1993).
RN [10]
RP INTERCHAIN DISULFIDE BOND.
RX PubMed=14732708; DOI=10.1074/jbc.M313446200;
RA Papadakis M., Hawkins L.M., Stephenson F.A.;
RT "Appropriate NR1-NR1 disulfide-linked homodimer formation is requisite
RT for efficient expression of functional, cell surface N-methyl-D-
RT aspartate NR1/NR2 receptors.";
RL J. Biol. Chem. 279:14703-14712(2004).
RN [11]
RP INTERACTION WITH MYZAP.
RX PubMed=18849881; DOI=10.1097/WNR.0b013e328317f05f;
RA Roginski R.S., Goubaeva F., Mikami M., Fried-Cassorla E., Nair M.R.,
RA Yang J.;
RT "GRINL1A colocalizes with N-methyl D-aspartate receptor NR1 subunit
RT and reduces N-methyl D-aspartate toxicity.";
RL NeuroReport 19:1721-1726(2008).
RN [12]
RP STRUCTURE BY NMR OF 599-621.
RX PubMed=10201407; DOI=10.1038/7610;
RA Opella S.J., Marassi F.M., Gesell J.J., Valente A.P., Kim Y.,
RA Oblatt-Montal M., Montal M.;
RT "Structures of the M2 channel-lining segments from nicotinic
RT acetylcholine and NMDA receptors by NMR spectroscopy.";
RL Nat. Struct. Biol. 6:374-379(1999).
RN [13]
RP VARIANTS MRD8 SER-560 INS AND LYS-662, AND CHARACTERIZATION OF
RP VARIANTS MRD8 SER-560 INS AND LYS-662.
RX PubMed=21376300; DOI=10.1016/j.ajhg.2011.02.001;
RA Hamdan F.F., Gauthier J., Araki Y., Lin D.T., Yoshizawa Y.,
RA Higashi K., Park A.R., Spiegelman D., Dobrzeniecka S., Piton A.,
RA Tomitori H., Daoud H., Massicotte C., Henrion E., Diallo O.,
RA Shekarabi M., Marineau C., Shevell M., Maranda B., Mitchell G.,
RA Nadeau A., D'Anjou G., Vanasse M., Srour M., Lafreniere R.G.,
RA Drapeau P., Lacaille J.C., Kim E., Lee J.R., Igarashi K.,
RA Huganir R.L., Rouleau G.A., Michaud J.L.;
RT "Excess of de novo deleterious mutations in genes associated with
RT glutamatergic systems in nonsyndromic intellectual disability.";
RL Am. J. Hum. Genet. 88:306-316(2011).
CC -!- FUNCTION: NMDA receptor subtype of glutamate-gated ion channels
CC with high calcium permeability and voltage-dependent sensitivity
CC to magnesium. Mediated by glycine. This protein plays a key role
CC in synaptic plasticity, synaptogenesis, excitotoxicity, memory
CC acquisition and learning. It mediates neuronal functions in
CC glutamate neurotransmission. Is involved in the cell surface
CC targeting of NMDA receptors (By similarity).
CC -!- SUBUNIT: Forms heteromeric channel of a zeta subunit (GRIN1), a
CC epsilon subunit (GRIN2A, GRIN2B, GRIN2C or GRIN2D) and a third
CC subunit (GRIN3A or GRIN3B); disulfide-linked. Found in a complex
CC with GRIN2A or GRIN2B, GRIN3A or GRIN3B and PPP2CB. Interacts with
CC DLG4 and MPDZ. Interacts with SNX27 (via PDZ domain); the
CC interaction is required for recycling to the plasma membrane when
CC endocytosed and prevent degradation in lysosomes (By similarity).
CC Interacts with LRFN1 and LRFN2 (By similarity). Interacts with
CC MYZAP.
CC -!- INTERACTION:
CC Q62936:Dlg3 (xeno); NbExp=3; IntAct=EBI-8286218, EBI-349596;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein
CC (By similarity). Cell junction, synapse, postsynaptic cell
CC membrane (By similarity). Cell junction, synapse, postsynaptic
CC cell membrane, postsynaptic density (By similarity). Note=Enriched
CC in postsynaptic plasma membrane and postsynaptic densities (By
CC similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=3; Synonyms=Long, NR1-3;
CC IsoId=Q05586-1; Sequence=Displayed;
CC Name=1; Synonyms=Short, NR1-1;
CC IsoId=Q05586-2; Sequence=VSP_000137, VSP_000138;
CC Name=2; Synonyms=Medium, NR1-2;
CC IsoId=Q05586-3; Sequence=VSP_000139;
CC Name=4;
CC IsoId=Q05586-4; Sequence=VSP_011778, VSP_011779;
CC Name=5;
CC IsoId=Q05586-5; Sequence=VSP_011777;
CC Name=6;
CC IsoId=Q05586-6; Sequence=VSP_011777, VSP_011778, VSP_011779;
CC Name=7;
CC IsoId=Q05586-7; Sequence=VSP_011777, VSP_045464;
CC -!- PTM: NMDA is probably regulated by C-terminal phosphorylation of
CC an isoform of NR1 by PKC. Dephosphorylated on Ser-897 probably by
CC protein phosphatase 2A (PPP2CB). Its phosphorylated state is
CC influenced by the formation of the NMDAR-PPP2CB complex and the
CC NMDAR channel activity.
CC -!- DISEASE: Mental retardation, autosomal dominant 8 (MRD8)
CC [MIM:614254]: A disorder characterized by significantly below
CC average general intellectual functioning associated with
CC impairments in adaptive behavior and manifested during the
CC developmental period. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the glutamate-gated ion channel
CC (TC 1.A.10.1) family. NR1/GRIN1 subfamily.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=NMDA receptor entry;
CC URL="http://en.wikipedia.org/wiki/NMDA_receptor";
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DR EMBL; L13266; AAB59360.1; -; mRNA.
DR EMBL; L13267; AAA36198.1; -; mRNA.
DR EMBL; L13268; AAB59361.1; -; mRNA.
DR EMBL; D13515; BAA02732.1; -; mRNA.
DR EMBL; L05666; AAA21180.1; -; mRNA.
DR EMBL; AF015730; AAB67723.1; -; mRNA.
DR EMBL; AF015731; AAB67724.1; -; mRNA.
DR EMBL; Z32772; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; Z32773; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; Z32774; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL929554; CAH72874.2; -; Genomic_DNA.
DR EMBL; AL929554; CAH72875.2; -; Genomic_DNA.
DR EMBL; AL929554; CAH72876.2; -; Genomic_DNA.
DR EMBL; AL929554; CAH72879.2; -; Genomic_DNA.
DR EMBL; U08106; AAA62111.1; -; mRNA.
DR EMBL; U08107; AAA62112.1; -; mRNA.
DR EMBL; S57708; AAB25917.1; -; mRNA.
DR PIR; A46612; A46612.
DR PIR; A47551; A47551.
DR RefSeq; NP_000823.4; NM_000832.6.
DR RefSeq; NP_001172019.1; NM_001185090.1.
DR RefSeq; NP_001172020.1; NM_001185091.1.
DR RefSeq; NP_015566.1; NM_007327.3.
DR RefSeq; NP_067544.1; NM_021569.3.
DR RefSeq; XP_005266128.1; XM_005266071.1.
DR RefSeq; XP_005266130.1; XM_005266073.1.
DR UniGene; Hs.558334; -.
DR PDB; 2HQW; X-ray; 1.90 A; B=875-898.
DR PDB; 2NR1; NMR; -; A=599-621.
DR PDB; 3BYA; X-ray; 1.85 A; B=875-898.
DR PDBsum; 2HQW; -.
DR PDBsum; 2NR1; -.
DR PDBsum; 3BYA; -.
DR ProteinModelPortal; Q05586; -.
DR SMR; Q05586; 24-838.
DR IntAct; Q05586; 7.
DR MINT; MINT-1900224; -.
DR BindingDB; Q05586; -.
DR ChEMBL; CHEMBL2015; -.
DR DrugBank; DB00142; L-Glutamic Acid.
DR DrugBank; DB01173; Orphenadrine.
DR GuidetoPHARMACOLOGY; 455; -.
DR TCDB; 1.A.10.1.6; the glutamate-gated ion channel (gic) family of neurotransmitter receptors.
DR PhosphoSite; Q05586; -.
DR DMDM; 548377; -.
DR PaxDb; Q05586; -.
DR PRIDE; Q05586; -.
DR Ensembl; ENST00000315048; ENSP00000316696; ENSG00000176884.
DR Ensembl; ENST00000371546; ENSP00000360601; ENSG00000176884.
DR Ensembl; ENST00000371550; ENSP00000360605; ENSG00000176884.
DR Ensembl; ENST00000371553; ENSP00000360608; ENSG00000176884.
DR Ensembl; ENST00000371559; ENSP00000360614; ENSG00000176884.
DR Ensembl; ENST00000371560; ENSP00000360615; ENSG00000176884.
DR Ensembl; ENST00000371561; ENSP00000360616; ENSG00000176884.
DR GeneID; 2902; -.
DR KEGG; hsa:2902; -.
DR UCSC; uc004clk.3; human.
DR CTD; 2902; -.
DR GeneCards; GC09P140032; -.
DR HGNC; HGNC:4584; GRIN1.
DR HPA; CAB006831; -.
DR MIM; 138249; gene.
DR MIM; 614254; phenotype.
DR neXtProt; NX_Q05586; -.
DR Orphanet; 178469; Autosomal dominant nonsyndromic intellectual deficit.
DR PharmGKB; PA28978; -.
DR eggNOG; NOG282132; -.
DR HOVERGEN; HBG052638; -.
DR KO; K05208; -.
DR OMA; WNHVILL; -.
DR OrthoDB; EOG79GT5V; -.
DR PhylomeDB; Q05586; -.
DR Reactome; REACT_13685; Neuronal System.
DR SignaLink; Q05586; -.
DR ChiTaRS; GRIN1; human.
DR EvolutionaryTrace; Q05586; -.
DR GeneWiki; GRIN1; -.
DR GenomeRNAi; 2902; -.
DR NextBio; 11487; -.
DR PMAP-CutDB; Q5VSF3; -.
DR PRO; PR:Q05586; -.
DR ArrayExpress; Q05586; -.
DR Bgee; Q05586; -.
DR CleanEx; HS_GRIN1; -.
DR Genevestigator; Q05586; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0009986; C:cell surface; ISS:BHF-UCL.
DR GO; GO:0032590; C:dendrite membrane; IEA:Ensembl.
DR GO; GO:0043197; C:dendritic spine; ISS:BHF-UCL.
DR GO; GO:0060076; C:excitatory synapse; ISS:BHF-UCL.
DR GO; GO:0017146; C:N-methyl-D-aspartate selective glutamate receptor complex; IDA:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB.
DR GO; GO:0045211; C:postsynaptic membrane; ISS:UniProtKB.
DR GO; GO:0043083; C:synaptic cleft; ISS:BHF-UCL.
DR GO; GO:0008021; C:synaptic vesicle; ISS:UniProtKB.
DR GO; GO:0043195; C:terminal bouton; ISS:BHF-UCL.
DR GO; GO:0005262; F:calcium channel activity; IEA:Ensembl.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0005516; F:calmodulin binding; ISS:UniProtKB.
DR GO; GO:0005234; F:extracellular-glutamate-gated ion channel activity; IEA:InterPro.
DR GO; GO:0016595; F:glutamate binding; IDA:UniProtKB.
DR GO; GO:0016594; F:glycine binding; IDA:UniProtKB.
DR GO; GO:0004972; F:N-methyl-D-aspartate selective glutamate receptor activity; IEA:Ensembl.
DR GO; GO:0042165; F:neurotransmitter binding; ISS:BHF-UCL.
DR GO; GO:0022843; F:voltage-gated cation channel activity; IEA:Ensembl.
DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl.
DR GO; GO:0055074; P:calcium ion homeostasis; ISS:UniProtKB.
DR GO; GO:0006812; P:cation transport; IDA:UniProtKB.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0071287; P:cellular response to manganese ion; IEA:Ensembl.
DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR GO; GO:0001661; P:conditioned taste aversion; IEA:Ensembl.
DR GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0007616; P:long-term memory; IEA:Ensembl.
DR GO; GO:0060179; P:male mating behavior; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0008355; P:olfactory learning; IEA:Ensembl.
DR GO; GO:0021586; P:pons maturation; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:2000463; P:positive regulation of excitatory postsynaptic membrane potential; ISS:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; ISS:UniProtKB.
DR GO; GO:0060134; P:prepulse inhibition; IEA:Ensembl.
DR GO; GO:0018964; P:propylene metabolic process; ISS:BHF-UCL.
DR GO; GO:0050770; P:regulation of axonogenesis; IEA:Ensembl.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; IEA:Ensembl.
DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl.
DR GO; GO:0043576; P:regulation of respiratory gaseous exchange; IEA:Ensembl.
DR GO; GO:0051963; P:regulation of synapse assembly; IEA:Ensembl.
DR GO; GO:0007585; P:respiratory gaseous exchange; IEA:Ensembl.
DR GO; GO:0001975; P:response to amphetamine; IEA:Ensembl.
DR GO; GO:0051592; P:response to calcium ion; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IDA:UniProtKB.
DR GO; GO:0060992; P:response to fungicide; IEA:Ensembl.
DR GO; GO:0043278; P:response to morphine; IEA:Ensembl.
DR GO; GO:0048511; P:rhythmic process; IEA:Ensembl.
DR GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl.
DR GO; GO:0035176; P:social behavior; IEA:Ensembl.
DR GO; GO:0001967; P:suckling behavior; IEA:Ensembl.
DR GO; GO:0035249; P:synaptic transmission, glutamatergic; IEA:Ensembl.
DR GO; GO:0008542; P:visual learning; ISS:UniProtKB.
DR InterPro; IPR001828; ANF_lig-bd_rcpt.
DR InterPro; IPR018882; CaM-bd_C0_NMDA_rcpt_NR1.
DR InterPro; IPR019594; Glu_rcpt_Glu/Gly-bd.
DR InterPro; IPR001320; Iontro_glu_rcpt.
DR InterPro; IPR001508; NMDA_rcpt.
DR InterPro; IPR028082; Peripla_BP_I.
DR InterPro; IPR001638; SBP_bac_3.
DR Pfam; PF01094; ANF_receptor; 1.
DR Pfam; PF10562; CaM_bdg_C0; 1.
DR Pfam; PF00060; Lig_chan; 1.
DR Pfam; PF00497; SBP_bac_3; 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 3D-structure; Alternative splicing; Calcium; Cell junction;
KW Cell membrane; Complete proteome; Disease mutation; Disulfide bond;
KW Glycoprotein; Ion channel; Ion transport; Ligand-gated ion channel;
KW Magnesium; Membrane; Mental retardation; Phosphoprotein; Polymorphism;
KW Postsynaptic cell membrane; Receptor; Reference proteome; Signal;
KW Synapse; Transmembrane; Transmembrane helix; Transport.
FT SIGNAL 1 18 Potential.
FT CHAIN 19 938 Glutamate receptor ionotropic, NMDA 1.
FT /FTId=PRO_0000011587.
FT TOPO_DOM 19 559 Extracellular (Potential).
FT TRANSMEM 560 580 Helical; (Potential).
FT TOPO_DOM 581 636 Cytoplasmic (Potential).
FT TRANSMEM 637 657 Helical; (Potential).
FT TOPO_DOM 658 812 Extracellular (Potential).
FT TRANSMEM 813 833 Helical; (Potential).
FT TOPO_DOM 834 938 Cytoplasmic (Potential).
FT REGION 516 518 Glycine binding (By similarity).
FT BINDING 523 523 Glycine (By similarity).
FT BINDING 688 688 Glycine (By similarity).
FT BINDING 732 732 Glycine (By similarity).
FT MOD_RES 889 889 Phosphoserine; by PKC (Probable).
FT MOD_RES 890 890 Phosphoserine; by PKC (Probable).
FT MOD_RES 896 896 Phosphoserine; by PKC (Probable).
FT MOD_RES 897 897 Phosphoserine; by PKC (Probable).
FT CARBOHYD 61 61 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 203 203 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 239 239 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 276 276 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 300 300 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 350 350 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 368 368 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 440 440 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 471 471 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 491 491 N-linked (GlcNAc...) (Potential).
FT DISULFID 79 79 Interchain.
FT VAR_SEQ 190 190 K -> KSKKRNYENLDQLSYDNKRGPK (in isoform
FT 5, isoform 6 and isoform 7).
FT /FTId=VSP_011777.
FT VAR_SEQ 864 938 DRKSGRAEPDPKKKATFRAITSTLASSFKRRRSSKDTSTGG
FT GRGALQNQKDTVLPRRAIEREEGQLQLCSRHRES -> QYH
FT PTDITGPLNLSDPSVSTVV (in isoform 7).
FT /FTId=VSP_045464.
FT VAR_SEQ 864 900 Missing (in isoform 2).
FT /FTId=VSP_000139.
FT VAR_SEQ 864 885 DRKSGRAEPDPKKKATFRAITS -> QYHPTDITGPLNLSD
FT PSVSTVV (in isoform 1).
FT /FTId=VSP_000137.
FT VAR_SEQ 886 938 Missing (in isoform 1).
FT /FTId=VSP_000138.
FT VAR_SEQ 901 922 STGGGRGALQNQKDTVLPRRAI -> QYHPTDITGPLNLSD
FT PSVSTVV (in isoform 4 and isoform 6).
FT /FTId=VSP_011778.
FT VAR_SEQ 923 938 Missing (in isoform 4 and isoform 6).
FT /FTId=VSP_011779.
FT VARIANT 540 540 I -> M (in dbSNP:rs3181457).
FT /FTId=VAR_049187.
FT VARIANT 560 560 S -> SS (in MRD8; there is near abolition
FT of the activity of the NMDA receptor in
FT Xenopus oocytes; alters the 3-dimensional
FT structure at the receptor's channel pore
FT entrance).
FT /FTId=VAR_066597.
FT VARIANT 662 662 E -> K (in MRD8; this mutation produces a
FT significant increase in NMDA receptor-
FT induced calcium currents; excessive
FT calcium influx through NMDA receptor
FT could lead to excitotoxic neuronal cell
FT damage).
FT /FTId=VAR_066598.
FT VARIANT 682 682 A -> S (in dbSNP:rs1126448).
FT /FTId=VAR_069057.
FT CONFLICT 389 389 P -> S (in Ref. 8; AAB25917).
FT CONFLICT 488 488 E -> K (in Ref. 1; AAB59361).
FT HELIX 600 620
FT HELIX 877 892
SQ SEQUENCE 938 AA; 105373 MW; CDF5402769E530AB CRC64;
MSTMRLLTLA LLFSCSVARA ACDPKIVNIG AVLSTRKHEQ MFREAVNQAN KRHGSWKIQL
NATSVTHKPN AIQMALSVCE DLISSQVYAI LVSHPPTPND HFTPTPVSYT AGFYRIPVLG
LTTRMSIYSD KSIHLSFLRT VPPYSHQSSV WFEMMRVYSW NHIILLVSDD HEGRAAQKRL
ETLLEERESK AEKVLQFDPG TKNVTALLME AKELEARVII LSASEDDAAT VYRAAAMLNM
TGSGYVWLVG EREISGNALR YAPDGILGLQ LINGKNESAH ISDAVGVVAQ AVHELLEKEN
ITDPPRGCVG NTNIWKTGPL FKRVLMSSKY ADGVTGRVEF NEDGDRKFAN YSIMNLQNRK
LVQVGIYNGT HVIPNDRKII WPGGETEKPR GYQMSTRLKI VTIHQEPFVY VKPTLSDGTC
KEEFTVNGDP VKKVICTGPN DTSPGSPRHT VPQCCYGFCI DLLIKLARTM NFTYEVHLVA
DGKFGTQERV NNSNKKEWNG MMGELLSGQA DMIVAPLTIN NERAQYIEFS KPFKYQGLTI
LVKKEIPRST LDSFMQPFQS TLWLLVGLSV HVVAVMLYLL DRFSPFGRFK VNSEEEEEDA
LTLSSAMWFS WGVLLNSGIG EGAPRSFSAR ILGMVWAGFA MIIVASYTAN LAAFLVLDRP
EERITGINDP RLRNPSDKFI YATVKQSSVD IYFRRQVELS TMYRHMEKHN YESAAEAIQA
VRDNKLHAFI WDSAVLEFEA SQKCDLVTTG ELFFRSGFGI GMRKDSPWKQ NVSLSILKSH
ENGFMEDLDK TWVRYQECDS RSNAPATLTF ENMAGVFMLV AGGIVAGIFL IFIEIAYKRH
KDARRKQMQL AFAAVNVWRK NLQDRKSGRA EPDPKKKATF RAITSTLASS FKRRRSSKDT
STGGGRGALQ NQKDTVLPRR AIEREEGQLQ LCSRHRES
//
MIM
138249
*RECORD*
*FIELD* NO
138249
*FIELD* TI
*138249 GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 1; GRIN1
;;N-METHYL-D-ASPARTATE RECEPTOR CHANNEL, SUBUNIT ZETA-1; NMDAR1;;
read moreNR1
*FIELD* TX
CLONING
Glutamate receptors are the predominant excitatory neurotransmitter
receptors in the mammalian brain and are activated in a variety of
normal neurophysiologic processes. The classification of glutamate
receptors is based on their activation by different pharmacologic
agonists. Thus, 1 class, the NMDA receptors, have N-methyl-D-aspartate
as an agonist. Moriyoshi et al. (1991) cloned and characterized a cDNA
encoding the rat NMDA receptor. The protein had a significant sequence
similarity to the AMPA/kainate receptors (see 600282) and contained 4
putative transmembrane segments following a large extracellular domain.
The NMDA receptor mRNA was expressed in neuronal cells throughout the
brain, particularly in the hippocampus, cerebral cortex, and cerebellum.
Kumar et al. (1991) isolated and characterized a protein complex of 4
major proteins that represent an intact complex of the NMDA receptor ion
channel. Furthermore, they cloned the cDNA for one of the subunits of
this receptor complex, the glutamate-binding protein, from rat brain;
see 138251.
Karp et al. (1993) cloned a cDNA encoding the key subunit of the human
NMDA receptor, NMDAR1. It encodes a 938-amino acid protein which showed
high evolutionary conservation in structure and physiologic properties.
The 8 splice variants of vertebrate NR1 have 4 different C-terminal
cytoplasmic tails consisting of different combinations of C-terminal
cassettes, designated C0, C1, C2, and C2-prime. By functional assays and
sequence analysis, Standley et al. (2000) identified an endoplasmic
reticulum (ER) retention signal in the C1 cassette. They also found a
PDZ-interacting domain in the C2-prime cassette that could mask the ER
retention of the C1 cassette and lead to surface expression.
GENE STRUCTURE
Zimmer et al. (1995) cloned the human NMDAR1 gene and showed that it
consists of 21 exons distributed over about 31 kb. Three of the exons
that are alternatively spliced in the rat and which produce 8 isoforms
in that species were also present in the human sequence. The promoter
region contained 2 DNA binding sites for the homeobox proteins
'even-skipped' (see EVX1, 142996 and EVX2, 142991).
MAPPING
Karp et al. (1993) mapped the NMDAR1 gene to 9q34.3 by analysis of blot
hybridization of a DNA panel of human/hamster somatic cell hybrids and
by fluorescence in situ hybridization (FISH). By the same method,
Collins et al. (1993) mapped the NMDAR1 gene to 9q34.3 and Takano et al.
(1993) mapped the gene, which they referred to as the zeta-1 subunit, to
9q34. Collins et al. (1993) and Takano et al. (1993) pointed out that
the gene is a candidate for the site of the mutation in torsion dystonia
(see 128100).
Brett et al. (1994) also mapped the GRIN gene to 9q34.3 by FISH, using a
genomic clone. Cutting a panel of genomic DNAs with 20 restriction
enzymes, they demonstrated a VNTR sequence 5-prime to the gene that was
polymorphic for a number of the enzymes. Using one of these markers for
linkage analysis in the CEPH families, the GRIN1 gene was found to be
linked to D9S7 with a maximum lod score of 20.09 at zero recombination
in males and 0.03% recombination in females.
GENE FUNCTION
Following up on the studies in rodents and nonhuman primates (see later)
that linked the activity of NMDA receptors within the hippocampus to
animals' performance on memory-related tasks, Grunwald et al. (1999)
studied whether hippocampal NMDA receptors, most likely within the CA1
region, participate in human verbal memory processes. They presented
behavioral, anatomic, and electrophysiologic results indicating that
hippocampal NMDA receptors indeed are involved in human memory.
Hardingham et al. (2002) reported that synaptic and extrasynaptic NMDA
receptors have opposite effects on CREB (123810) function, gene
regulation, and neuronal survival. Calcium entry through synaptic NMDA
receptors induced CREB activity and brain-derived neurotrophic factor
(BDNF; 113505) gene expression as strongly as did stimulation of L-type
calcium channels. In contrast, calcium entry through extrasynaptic NMDA
receptors, triggered by bath glutamate exposure or hypoxic/ischemic
conditions, activated a general and dominant CREB shut-off pathway that
blocked induction of BDNF expression. Synaptic NMDA receptors have
antiapoptotic activity, whereas stimulation of extrasynaptic NMDA
receptors caused loss of mitochondrial membrane potential (an early
marker for glutamate-induced neuronal damage) and cell death.
Sin et al. (2002) used in vivo time-lapse imaging of optic tectal cells
in Xenopus laevis tadpoles to demonstrate that enhanced visual activity
driven by a light stimulus promotes dendritic arbor growth. The
stimulus-induced dendritic arbor growth requires glutamate
receptor-mediated synaptic transmission, decreased RhoA (165390)
activity, and increased RAC (see 602048) and CDC42 (116952) activity.
Sin et al. (2002) concluded that their results delineated a role for Rho
GTPases in the structural plasticity driven by visual stimulation in
vivo.
Lee et al. (2002) reported that dopamine D1 receptors (126449) modulate
NMDA glutamate receptor-mediated functions through direct
protein-protein interactions. Two regions in the D1 receptor carboxyl
tail could directly and selectively couple to NMDA glutamate receptor
subunits NR1-1A and NR2A (138253). While one interaction was involved in
the inhibition of NMDA receptor-gated currents, the other was implicated
in the attenuation of NMDA receptor-mediated excitotoxicity through a
phosphatidylinositol 3-kinase (see 171833)-dependent pathway.
Nong et al. (2003) reported that stimulation of the glycine site of the
NMDA receptor initiates signaling through the NMDAR complex, priming the
receptors for clathrin-dependent endocytosis. Glycine binding alone does
not cause the receptor to be endocytosed; this requires both glycine and
glutamate site activation of NMDARs. The priming effect of glycine is
mimicked by the NMDAR glycine site agonist D-serine, and is blocked by
competitive glycine site antagonists. Synaptic as well as extrasynaptic
NMDARs are primed for internalization by glycine site stimulation. Nong
et al. (2003) concluded that their results demonstrated transmembrane
signal transduction through activating the glycine site of NMDARs, and
elucidated a model for modulating cell-cell communication in the central
nervous system.
By examining the kinetics of transmitter binding and channel gating in
single-channel currents from recombinant NR1/NR2A receptors, Popescu et
al. (2004) showed that the synaptic response to trains of impulses is
determined by the molecular reaction mechanism of the receptor. The rate
constants estimated for the activation reaction predicted that, after
binding neurotransmitter, receptors hesitate for approximately 4
milliseconds in a closed high-affinity conformation before they either
proceed towards opening or release neurotransmitter, with about equal
probabilities. Because only about half of the initial fully occupied
receptors become active, repetitive stimulation elicits currents with
distinct waveforms depending on the pulse frequency.
Karadottir et al. (2005) demonstrated that precursor, immature, and
mature oligodendrocytes in the white matter of the cerebellum and corpus
callosum exhibit NMDA-evoked currents, mediated by receptors that are
blocked only weakly by magnesium and that may contain NR1, NR2C
(138254), and NR3 (see 606650) NMDA receptor subunits. NMDA receptors
are present in the myelinating processes of oligodendrocytes, where the
small intracellular space could lead to a large rise in intracellular
ion concentration in response to NMDA receptor activation. Karadottir et
al. (2005) found that simulating ischemia led to development of an
inward current in oligodendrocytes, which was partly mediated by NMDA
receptors.
Salter and Fern (2005) independently showed NMDA receptor subunit
expression on oligodendrocyte processes and the presence of NMDA
receptor subunit mRNA in isolated white matter. NR1, NR2A (138253), NR2B
(138252), NR2C, NR2D, and NR3A subunits showed clustered expression in
cell processes, but NR3B (606651) was absent. During modeled ischemia,
NMDA receptor activation resulted in rapid calcium-dependent detachment
and disintegration of oligodendroglial processes in the white matter of
mice expressing green fluorescent protein (GFP) specifically in
oligodendrocytes. This effect occurred at mouse ages corresponding to
both the initiation and the conclusion of myelination. NR1 subunits were
found mainly in oligodendrocyte processes, whereas AMPA/kainate receptor
subunits (see 600282) were found mainly in the somata. Consistent with
this observation, injury to the somata was prevented by blocking
AMPA/kainate receptors, and preventing injury to oligodendroglial
processes required the blocking of NMDA receptors. Salter and Fern
(2005) suggested that the presence of NMDA receptors in oligodendrocyte
processes may explain why previous studies that focused on the somata
did not detect a role for NMDA receptors in oligodendrocyte injury.
These NMDA receptors bestow a high sensitivity to acute injury.
Tashiro et al. (2006) developed a retrovirus-mediated single-cell gene
knockout technique in mice and showed that the survival of new neurons
is competitively regulated by their own NMDA-type glutamate receptor
during a short, critical period soon after neuronal birth. This finding
indicated that the survival of new neurons and the resulting formation
of new circuits are regulated in an input-dependent, cell-specific
manner. Therefore, Tashiro et al. (2006) suggested that the circuits
formed by new neurons may represent information associated with input
activity within a short time window in the critical period. This
information-specific addition of new circuits through selective survival
or death of new neurons may be a unique attribute of new neurons that
enables them to play a critical role in learning and memory.
Micu et al. (2006) showed that NMDA glutamate receptors mediate calcium
ion accumulation in central myelin in response to chemical ischemia in
vitro. Using 2-photon microscopy, they imaged fluorescence of the
calcium ion indicator X-rhod-1 loaded into oligodendrocytes and the
cytoplasmic compartment of the myelin sheath in adult rat optic nerves.
The AMPA/kainate receptor antagonist NBQX completely blocked the
ischemic calcium ion increase in oligodendroglial cell bodies, but only
modestly reduced the calcium ion increase in myelin. In contrast, the
calcium ion increase in myelin was abolished by broad-spectrum NMDA
receptor antagonists but not by more selective blockers of NR2A and NR2B
subunit-containing receptors. In vitro ischemia causes ultrastructural
damage to both axon cylinders and myelin. NMDA receptor antagonism
greatly reduced the damage to myelin. NR1, NR2, and NR3 subunits were
detected in myelin by immunohistochemistry and immunoprecipitation,
indicating that all necessary subunits were present for the formation of
functional NMDA receptors. Micu et al. (2006) concluded that their data
showed that the mature myelin sheath can respond independently to
injurious stimuli. Given that axons are known to release glutamate, the
finding that the calcium ion increase is mediated in large part by
activation of myelinic NMDA receptors suggested a new mechanism of
axomyelinic signaling.
In mice, Clem et al. (2008) examined the effect of ongoing whisker
stimulation on synaptic strengthening at layer 4-2/3 synapses in the
barrel cortex. Although N-methyl-D-aspartate receptors were required to
initiate strengthening, they subsequently suppressed further
potentiation at these synapses in vitro and in vivo. Despite this
transition, synaptic strengthening continued with additional sensory
activity but instead required the activation of metabotropic glutamate
receptors (see 604473), suggesting a mechanism by which continued
experience can result in increasing synaptic strength over time.
Losonczy et al. (2008) demonstrated that the coupling between local
dendritic spikes and the soma of rat hippocampal CA1 pyramidal neurons
can be modified in a branch-specific manner through an NMDAR-dependent
regulation of dendritic Kv4.2 (605410) potassium channels. These data
suggested that compartmentalized changes in branch excitability could
store multiple complex features of synaptic input, such as their
spatiotemporal correlation. Losonczy et al. (2008) proposed that this
'branch strength potentiation' represents a previously unknown form of
information storage that is distinct from that produced by changes in
synaptic efficacy both at the mechanistic level and in the type of
information stored.
Henneberger et al. (2010) demonstrated that clamping internal calcium
ion in individual CA1 astrocytes of the hippocampus blocks long-term
potentiation (LTP) induction at nearby excitatory synapses by decreasing
the occupancy of the NMDAR coagonist sites by D-serine. This LTP
blockade can be reversed by exogenous D-serine or glycine, whereas
depletion of D-serine or disruption of exocytosis in an individual
astrocyte blocks local LTP. Henneberger et al. (2010) concluded that
calcium ion-dependent release of D-serine from an astrocyte controls
NMDAR-dependent plasticity in many thousands of excitatory synapses
nearby.
Using a self-paced operant task in which mice learn to perform a
particular sequence of actions to obtain an outcome, Jin and Costa
(2010) found neural activity in nigrostriatal circuits specifically
signaling the initiation or the termination of each action sequence.
This start/stop activity emerged during sequence learning, was specific
for particular actions, and did not reflect interval timing, movement
speed, or action value. Furthermore, genetically altering the function
of striatal circuits by developing a nigrostriatal-specific deletion of
the NMDAR1 gene disrupted the development of start/stop activity and
selectively impaired sequence learning. Jin and Costa (2010) concluded
that these results have important implications for understanding the
functional organization of actions and the sequence initiation and
termination impairments observed in basal ganglia disorders.
Attwood et al. (2011) demonstrated in mice that the serine protease
neuropsin (605644) is critical for stress-related plasticity in the
amygdala by regulating the dynamics of the EphB2 (605644)-NMDA receptor
interaction, the expression of Fkbp5 (602623) and anxiety-like behavior.
Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala,
causing dissociation of EphB2 from the NR1 subunit of the NMDA receptor
and promoting membrane turnover of EphB2 receptors. Dynamic EphB2-NR1
interaction enhances NMDA receptor current, induces Fkpb5 gene
expression, and enhances behavioral signatures of anxiety. On stress,
neuropsin-deficient mice do not show EphB2 cleavage and its dissociation
from NR1, resulting in a static EphB2-NR1 interaction, attenuated
induction of the Fkbp5 gene, and low anxiety. The behavioral response to
stress can be restored by intraamygdala injection of neuropsin into
neuropsin-deficient mice and disrupted by the injection of either
anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of
wildtype mice. Attwood et al. (2011) concluded that their findings
established a novel neuronal pathway linking stress-induced proteolysis
of EphB2 in the amygdala to anxiety.
BIOCHEMICAL FEATURES
- Crystal Structure
Furukawa et al. (2005) reported the crystal structure of the
ligand-binding core of NR2A (138253) with glutamate and that of the
NR1-NR2A heterodimer with glutamate and glycine. The NR2A-glutamate
complex defined the determinants of glutamate and NMDA recognition, and
the NR1-NR2A heterodimer suggested a mechanism for ligand-induced ion
channel opening. Analysis of the heterodimer interface, together with
biochemical and electrophysiologic experiments, confirmed that the
NR1-NR2A heterodimer is the functional unit in tetrameric NMDA receptors
and that tyr535 of NR1, located in the subunit interface, modulates the
rate of ion channel deactivation.
Karakas et al. (2011) reported that the GluN1 and GluN2B (138252)
amino-terminal domains forms a heterodimer and that phenylethanolamine
binds at the interface between GluN1 and GluNB2, rather than within the
GluN2B cleft. The crystal structure of the heterodimer formed between
the GluN1b amino-terminal domain from Xenopus laevis and the GluN2B
amino-terminal domain from Rattus norvegicus shows a highly distinct
pattern of subunit arrangement that is different from the arrangements
observed in homodimeric non-NMDA receptors and reveals the molecular
determinants for phenylethanolamine binding. Restriction of domain
movement in the bi-lobed structure of the GluN2B amino-terminal domain,
by engineering of an intersubunit disulfide bond, markedly decreased
sensitivity to ifenprodil, indicating that conformational freedom in the
GluN2B amino-terminal domain is essential for ifenprodil-mediated
allosteric inhibition of NMDA receptors. Karakas et al. (2011) concluded
that their findings paved the way for improving the design of
subtype-specific compounds with therapeutic value for neurologic
disorders and diseases.
MOLECULAR GENETICS
- Association with Schizophrenia Susceptibility
Rice et al. (2001) identified several polymorphisms in the GRIN1 gene,
including a 1001G-C change in the promoter region (dbSNP rs1114620), in
patients with schizophrenia (181500). Begni et al. (2003) investigated
the potential role of the 1001G-C polymorphism in susceptibility to
schizophrenia (181500) in a study of 139 Italian patients with
schizophrenia and 145 healthy control subjects. Sequence analysis
revealed that the C allele may alter the consensus sequence for the
transcription factor NF-kappa-B (164011) and that the frequency of this
allele was higher in patients than in control subjects (p = 0.0085). The
genotype distribution of the C allele was also different, with p =
0.034; if the C allele was considered dominant, the difference was more
significant, p = 0.0137. Begni et al. (2003) concluded that GRIN1 is a
good candidate gene for susceptibility to schizophrenia.
Zhao et al. (2006) genotyped 5 SNPs in GRIN1 in 2,455 schizophrenic and
nonschizophrenic Han Chinese subjects, including population- and
family-based samples, and performed case-control and transmission
disequilibrium test (TDT) analyses. A highly significant association
with schizophrenia was detected at the 5-prime end of GRIN1. Analysis of
single variants and multiple-locus haplotypes indicated that the
association is mainly generated by dbSNP rs11146020 (case-control study:
p = 0.0000013, OR = 0.61, 95% CI = 0.50-0.74; TDT: p = 0.0019, T/NT =
79/123).
- Mental Retardation
Hamdan et al. (2011) identified 2 mutations in GRIN1 resulting in
nonsyndromic intellectual disability (NSID) (MRD8; 614254) as a de novo
event. Both mutations resulted in decreased efficacy of the NMDAR
channel.
ANIMAL MODEL
It has long been hypothesized that memory storage in the mammalian brain
involves modifications of the synaptic connections between neurons. Hebb
(1949) introduced an important principle, known as the Hebb rule, that
of 'correlated activity': when the presynaptic and postsynaptic neurons
are active simultaneously, their connections become strengthened. Tsien
et al. (1996) reviewed reports suggesting that NMDARs can implement the
Hebb rule at the synaptic level and thus are crucial synaptic elements
for the induction of activity-dependent synaptic plasticity. Long-term
potentiation (LTP) is a widely used paradigm for increasing synaptic
efficiency, and its induction requires, in at least one of its forms,
the activation of NMDARs. The hippocampus is the most intensely studied
region for the importance of NMDARs in synaptic plasticity and memory.
Lesions of the hippocampus in humans and other mammals produce severe
amnesia for certain memories. Disruption of NMDARs in hippocampus leads
to blockade of synaptic plasticity and also to memory malfunction. Tsien
et al. (1996) produced a mouse strain in which the deletion of the
Nmdar1 gene was restricted to the CA1 pyramidal cells of the hippocampus
by use of a method that allowed CA1-restricted gene knockout. The mutant
mice grew into adulthood without obvious abnormalities. Adult mice
lacked NMDA receptor-mediated synaptic currents and long term
potentiation in the CA1 synapses and exhibited impaired spatial memory
but unimpaired nonspatial learning. Their results strongly suggested
that activity-dependent modifications of CA1 synapses, mediated by NMDA
receptors, play an essential role in the acquisition of spatial
memories.
In further studies of the CA1-specific Nmdar1 knockout mice, McHugh et
al. (1996) applied multiple electrode recording techniques to freely
behaving mice. They discovered that although the CA1 pyramidal cells of
these mice retain place-related activities, there is a significant
decrease in the spatial specificity of individual place fields. They
also found a striking deficit in the coordinated firing of pairs of
neurons tuned to similar spatial locations. Pairs had uncorrelated
firing even if their fields overlapped.
Rotenberg et al. (1996) studied the effects of an activated form
(CaMKII-Asp286) of Ca(2+)/calmodulin-dependent protein kinase (114078)
in transgenic mice. Normally, spatial location is encoded in the pattern
of firing of individual hippocampal pyramidal cells. When an animal
moves around in a familial environment, different place cells in the
hippocampus fire as the animal enters different regions of space.
Rotenberg et al. (1996) found that the CaMKII-Asp286 transgenic mice
lacked low frequency LTP and did not form stable 'place cells' in the
CA1 region of the hippocampus. Behaviorally, the mice were impaired in
spatial memory tasks.
By insertion of a neomycin resistance gene into intron 20 of the Nmdar1
gene, Mohn et al. (1999) generated mice expressing only 5% of normal
levels of the essential Nmdar1 subunit. Unlike Nmdar1 null mice, these
mice survived to adulthood and displayed behavioral abnormalities,
including increased motor activity and stereotypy and deficits in social
and sexual interactions. These behavioral alterations were similar to
those observed in pharmacologically induced animal models of
schizophrenia and could be ameliorated by treatment with haloperidol or
clozapine, antipsychotic drugs that antagonize dopaminergic and
serotonergic receptors. These findings supported a model in which
reduced NMDA receptor activity results in schizophrenic-like behavior
and revealed how pharmacologic manipulation of monoaminergic pathways
can affect this phenotype.
During et al. (2000) generated a recombinant adeno-associated virus
containing the NMDAR1 subunit and administered this vector orally to
rats. This vaccine generated polyclonal autoantibodies that targeted the
NMDAR1 subunit of the N-methyl-D-aspartate receptor. Transgene
expression persisted for at least 5 months and was associated with a
robust humoral response in the absence of a significant cell-mediated
response. The single-dose vaccine was associated with strong
antiepileptic and neuroprotective activity in rats for both a
kainate-induced seizure model and also a middle cerebral artery
occlusion stroke model at 1 to 5 months following vaccination. During et
al. (2000) concluded that a vaccination strategy targeting brain
proteins is feasible and may have therapeutic potential for neurologic
disorders.
Iwasato et al. (2000) generated mice in which the deletion of the Nmdar1
gene is restricted to excitatory cortical neurons, and demonstrated that
sensory periphery-related patterns develop normally in the brainstem and
thalamic somatosensory relay stations of these mice. In the
somatosensory cortex, thalamocortical afferents corresponding to large
whiskers formed patterns and display critical period plasticity, but
their patterning was not as distinct as that seen in the cortex of
normal mice. Other thalamocortical patterns corresponding to sinus hairs
and digits were mostly absent. The cellular aggregates known as barrels
and barrel boundaries did not develop, even at sites where
thalamocortical afferents cluster. Iwasato et al. (2000) concluded that
cortical NMDARs are essential for the aggregation of layer IV cells into
barrels and for development of the full complement of thalamocortical
patterns.
The hippocampal CA1 region is crucial for converting new memories into
long-term memories, a process believed to continue for weeks after
initial learning. Shimizu et al. (2000) developed an inducible,
reversible, and CA1-specific knockout technique to switch an NMDA
receptor function off or on in CA1 during the consolidation period in
mice. The data indicated that memory consolidation depends on the
reactivation of the NMDA receptor, possibly to reinforce site-specific
synaptic modifications to consolidate memory traces. Shimizu et al.
(2000) suggested that such a synaptic reinforcement process may also
serve as a cellular means by which the new memory is transferred from
the hippocampus to the cortex for permanent storage.
Nakazawa et al. (2002) generated and analyzed a genetically engineered
mouse strain in which the NMDA receptor gene is ablated specifically in
the CA3 pyramidal cells of adult mice. The mutant mice normally acquired
and retrieved spatial reference memory in the Morris water maze, but
they were impaired in retrieving this memory when presented with a
fraction of the original cues. Similarly, hippocampal CA1 pyramidal
cells in mutant mice displayed normal place-related activity in a
full-cue environment but showed a reduction in activity upon partial cue
removal. Nakazawa et al. (2002) concluded that their results provide
direct evidence for CA3 NMDA receptor involvement in associative memory
recall. Nakazawa et al. (2003) found that the mouse strain generated by
Nakazawa et al. (2002) showed impaired rapid acquisition of spatial
memory in the delayed matching-to-place version of the Morris water maze
task in which the animals are tested with novel locations of a hidden
platform. However, the animals were normal in recalling the memory of
familiar platform locations. Compared to control mice, the mutant mice
had larger CA1 place field sizes in novel environments, but not in
familiar environments. The authors concluded that CA3 NMDA receptors
play a role in rapid hippocampal encoding of novel information for the
learning of a one-time experience.
Cui et al. (2004) generated mice in which Nr1 can be temporarily
switched off in the forebrain by doxycycline treatment. Nine months
after conditioned fear training, untreated mice showed normal memory
retention. However, mice with transient inactivation of Nr1 for 30 days
starting at 6 months after initial training had defective memory
retention at 9 months. In subsequent tasks after the 9-month test
period, these mice showed normal learning and memory function. Cui et
al. (2004) suggested that the NMDA receptor is required for the ongoing
preservation of long-term memory storage.
Deng et al. (2006) observed that mice with striatum-specific Nmdar1
knockout using the CRE-loxP system showed impaired motor learning on the
rotarod test compared to wildtype mice. No differences were observed
between the 2 groups in inhibitory avoidance tests thought to involve
the amygdala and hippocampus. In vitro studies of neurons from these
mice showed absence of Nmdar-mediated currents, disruption of dorsal
striatal long-term potentiation, and disruption of ventral striatal
long-term depression. The findings suggested that the striatum is
involved in a subset of motor learning.
*FIELD* AV
.0001
MENTAL RETARDATION, AUTOSOMAL DOMINANT 8
GRIN1, GLU662LYS
In a 10-year-old female with moderate mental retardation (MRD8; 614254),
Hamdan et al. (2011) identified a heterozygous G-to-A transition at
nucleotide 1984 of the GRIN1 gene, resulting in a glu-to-lys
substitution at codon 662 (E662K). The mutation occurred de novo. The
patient had a normal neural exam and normal brain imaging by CT scan,
and there was no evidence of epilepsy. Functional studies in Xenopus
oocytes showed that this mutation produced a significant increase in
NMDAR-induced calcium currents; excessive calcium influx through NMDAR
could lead to excitotoxic neuronal cell damage. This mutation was not
identified in 285 healthy controls.
.0002
MENTAL RETARDATION, AUTOSOMAL DOMINANT 8
GRIN1, 3-BP DUP, SER560
In a 7.5-year-old boy with severe mental retardation (MRD8; 614254),
Hamdan et al. (2011) identified a duplication of 3 nucleotides between
positions 1679 and 1681 in the GRIN1 cDNA (1679_1681dup), resulting in
duplication of serine at codon 560 (ser560dup). The mutation was
identified de novo in the patient and was not seen in 285 control
chromosomes. The patient had partial complex seizures, hypotonia, and
normal brain imaging by MRI. Functional studies showed near abolition of
the activity of the NMDA receptor in Xenopus oocytes. The duplication at
codon 560 altered the 3-dimensional structure at the receptor's channel
pore entrance.
*FIELD* RF
1. Attwood, B. K.; Bourgognon, J.-M.; Patel, S.; Mucha, M.; Schiavon,
E.; Skrzypiec, A. E.; Young, K. W.; Shiosaka, S.; Korostynski, M.;
Piechota, M.; Przewlocki, R.; Pawlak, R.: Neuropsin cleaves EphB2
in the amygdala to control anxiety. Nature 473: 372-375, 2011.
2. Begni, S.; Moraschi, S.; Bignotti, S.; Fumagalli, F.; Rillosi,
L.; Perez, J.; Gennarelli, M.: Association between the G1001C polymorphism
in the GRIN1 gene promoter region and schizophrenia. Biol. Psychiat. 53:
617-619, 2003.
3. Brett, P. M.; Le Bourdelles, B.; See, C. G.; Whiting, P. J.; Attwood,
J.; Woodward, K.; Robertson, M. M.; Kalsi, G.; Povey, S.; Gurling,
H. M. D.: Genomic cloning and localization by FISH and linkage analysis
of the human gene encoding the primary subunit NMDAR1 (GRIN1) of the
NMDA receptor channel. Ann. Hum. Genet. 58: 95-100, 1994.
4. Clem, R. L.; Celikel, T.; Barth, A. L.: Ongoing in vivo experience
triggers synaptic metaplasticity in the neocortex. Science 319:
101-104, 2008.
5. Collins, C.; Duff, C.; Duncan, A. M. V.; Planells-Cases, R.; Sun,
W.; Norremolle, A.; Michaelis, E.; Montal, M.; Worton, R.; Hayden,
M. R.: Mapping of the human NMDA receptor subunit (NMDAR1) and the
proposed NMDA receptor glutamate-binding subunit (NMDARA1) to chromosomes
9q34.3 and chromosome 8, respectively. Genomics 17: 237-239, 1993.
6. Cui, Z.; Wang, H.; Tan, Y.; Zaia, K. A.; Zhang, S.; Tsien, J. Z.
: Inducible and reversible NR1 knockout reveals crucial role of the
NMDA receptor in preserving remote memories in the brain. Neuron 41:
781-793, 2004.
7. Deng, M. T.; Yokoi, F.; Yin, H. H.; Lovinger, D. M.; Wang, Y.;
Li, Y.: Disrupted motor learning and long-term synaptic plasticity
in mice lacking NMDAR1 in the striatum. Proc. Nat. Acad. Sci. 103:
15254-15259, 2006.
8. During, M. J.; Symes, C. W.; Lawlor, P. A.; Lin, J.; Dunning, J.;
Fitzsimons, H. L.; Poulsen, D.; Leone, P.; Xu, R.; Dicker, B. L.;
Lipski, J.; Young, D.: An oral vaccine against NMDAR1 with efficacy
in experimental stroke and epilepsy. Science 287: 1453-1460, 2000.
9. Furukawa, H.; Singh, S. K.; Mancusso, R.; Gouaux, E.: Subunit
arrangement and function in NMDA receptors. Nature 438: 185-192,
2005.
10. Grunwald, T.; Beck, H.; Lehnertz, K.; Blumcke, I.; Pezer, N.;
Kurthen, M.; Fernandez, G.; Van Roost, D.; Heinze, H. J.; Kutas, M.;
Elger, C. E.: Evidence relating human verbal memory to hippocampal
N-methyl-D-aspartate receptors. Proc. Nat. Acad. Sci. 96: 12085-12089,
1999.
11. Hamdan, F. F.; Gauthier, J.; Araki, Y.; Lin, D.-T.; Yoshizawa,
Y.; Higashi, K.; Park, A.-R.; Spiegelman, D.; Dobrzeniecka, S.; Piton,
A.; Tomitori, H.; Daoud, H.; and 22 others: Excess of de novo deleterious
mutations in genes associated with glutamatergic systems in nonsyndromic
intellectual disability. Am. J. Hum. Genet. 88: 306-316, 2011. Note:
Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.
12. Hardingham, G. E.; Fukunaga, Y.; Bading, H.: Extrasynaptic NMDARs
oppose synaptic NMDARs by triggering CREB shut-off and cell death
pathways. Nature Neurosci. 5: 405-414, 2002.
13. Hebb, D. O.: The Organization of Behavior: A Neuropsychological
Theory. New York: John Wiley , 1949.
14. Henneberger, C.; Papouin, T.; Oliet, S. H. R.; Rusakov, D. A.
: Long-term potentiation depends on release of D-serine from astrocytes. Nature 463:
232-236, 2010.
15. Iwasato, T.; Datwani, A.; Wolf, A. M.; Nishiyama, H.; Taguchi,
Y.; Tonegawa, S.; Knopfel, T.; Erzurumlu, R. S.; Itohara, S.: Cortex-restricted
disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 406:
726-731, 2000.
16. Jin, X.; Costa, R. M.: Start/stop signals emerge in nigrostriatal
circuits during sequence learning. Nature 466: 457-462, 2010.
17. Karadottir, R.; Cavelier, P.; Bergersen, L. H.; Attwell, D.:
NMDA receptors are expressed in oligodendrocytes and activated in
ischaemia. Nature 438: 1162-1166, 2005.
18. Karakas, E.; Simorowski, N.; Furukawa, H.: Subunit arrangement
and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. Nature 475:
249-253, 2011.
19. Karp, S. J.; Masu, M.; Eki, T.; Ozawa, K.; Nakanishi, S.: Molecular
cloning and chromosomal localization of the key subunit of the human
N-methyl-D-aspartate receptor. J. Biol. Chem. 268: 3728-3733, 1993.
20. Kumar, K. N.; Tilakaratne, N.; Johnson, P. S.; Allen, A. E.; Michaelis,
E. K.: Cloning of cDNA for the glutamate-binding subunit of an NMDA
receptor complex. Nature 354: 70-73, 1991.
21. Lee, F. J. S.; Xue, S.; Pei, L.; Vukusic, B.; Chery, N.; Wang,
Y.; Wang, Y. T.; Niznik, H. B.; Yu, X.; Liu, F.: Dual recognition
of NMDA receptor functions by direct protein-protein interactions
with the dopamine D1 receptor. Cell 111: 219-230, 2002.
22. Losonczy, A.; Makara, J. K.; Magee, J. C.: Compartmentalized
dendritic plasticity and input feature storage in neurons. Nature 452:
436-441, 2008.
23. McHugh, T. J.; Blum, K. I.; Tsien, J. Z.; Tonegawa, S.; Wilson,
M. A.: Impaired hippocampal representation of space in CA1-specific
NMDAR1 knockout mice. Cell 87: 1339-1349, 1996.
24. Micu, I.; Jiang, Q.; Coderre, E.; Ridsdale, A.; Zhang, L.; Woulfe,
J.; Yin, X.; Trapp, B. D.; McRory, J. E.; Rehak, R.; Zamponi, G. W.;
Wang, W.; Stys, P. K.: NMDA receptors mediate calcium accumulation
in myelin during chemical ischaemia. Nature 439: 988-992, 2006.
25. Mohn, A. R.; Gainetdinov, R. R.; Caron, M. G.; Koller, B. H.:
Mice with reduced NMDA receptor expression display behaviors related
to schizophrenia. Cell 98: 427-436, 1999.
26. Moriyoshi, K.; Masu, M.; Ishii, T.; Shigemoto, R.; Mizuno, N.;
Nakanishi, S.: Molecular cloning and characterization of the rat
NMDA receptor. Nature 354: 31-37, 1991.
27. Nakazawa, K.; Quirk, M. C.; Chitwood, R. A.; Watanabe, M.; Yeckel,
M. F.; Sun, L. D.; Kato, A.; Carr, C. A.; Johnston, D.; Wilson, M.
A.; Tonegawa, S.: Requirement for hippocampal CA3 NMDA receptors
in associative memory recall. Science 297: 211-218, 2002.
28. Nakazawa, K.; Sun, L. D.; Quirk, M. C.; Rondi-Reig, L.; Wilson,
M. A.; Tonegawa, S.: Hippocampal CA3 NMDA receptors are crucial for
memory acquisition of one-time experience. Neuron 38: 305-315, 2003.
29. Nong, Y.; Huang, Y.-Q.; Ju, W.; Kalia, L. V.; Ahmadian, G.; Wang,
Y. T.; Salter, M. W.: Glycine binding primes NMDA receptor internalization. Nature 422:
302-307, 2003.
30. Popescu, G.; Robert, A.; Howe, J. R.; Auerbach, A.: Reaction
mechanism determines NMDA receptor response to repetitive stimulation. Nature 430:
790-793, 2004.
31. Rice, S. R.; Niu, N.; Berman, D. B.; Heston, L. L.; Sobell, J.
L.: Identification of single nucleotide polymorphisms (SNPs) and
other sequence changes and estimation of nucleotide diversity in coding
and flanking regions of the NMDAR1 receptor gene in schizophrenic
patients. Molec. Psychiat. 6: 274-284, 2001.
32. Rotenberg, A.; Mayford, M.; Hawkins, R. D.; Kandel, E. R.; Muller,
R. U.: Mice expressing activated CaMKII lack low frequency LTP and
do not form stable place cells in the CA1 region of the hippocampus. Cell 87:
1351-1361, 1996.
33. Salter, M. G.; Fern, R.: NMDA receptors are expressed in developing
oligodendrocyte processes and mediate injury. Nature 438: 1167-1171,
2005.
34. Shimizu, E.; Tang, Y.-P.; Rampon, C.; Tsien, J. Z.: NMDA receptor-dependent
synaptic reinforcement as a crucial process for memory consolidation. Science 290:
1170-1174, 2000. Note: Erratum: Science 291: 1902 only, 2001.
35. Sin, W. C.; Haas, K.; Ruthazer, E. S.; Cline, H. T.: Dendrite
growth increased by visual activity requires NMDA receptor and Rho
GTPases. Nature 419: 475-480, 2002.
36. Standley, S.; Roche, K. W.; McCallum, J.; Sans, N.; Wenthold,
R. J.: PDZ domain suppression of an ER retention signal in NMDA receptor
NR1 splice variants. Neuron 28: 887-898, 2000.
37. Takano, H.; Onodera, O.; Tanaka, H.; Mori, H.; Sakimura, K.; Hori,
T.; Kobayashi, H.; Mishina, M.; Tsuji, S.: Chromosomal localization
of the epsilon-1, epsilon-3, and zeta-1 subunit genes of the human
NMDA receptor channel. Biochem. Biophys. Res. Commun. 197: 922-926,
1993.
38. Tashiro, A.; Sandler, V. M.; Toni, N.; Zhao, C.; Gage, F. H.:
NMDA-receptor-mediated, cell-specific integration of new neurons in
adult dentate gyrus. Nature 442: 929-933, 2006.
39. Tsien, J. Z.; Huerta, P. T.; Tonegawa, S.: The essential role
of hippocampal CA1 NMDA-receptor-dependent synaptic plasticity in
spatial memory. Cell 87: 1327-1338, 1996.
40. Zhao, X.; Li, H.; Shi, Y.; Tang, R.; Chen, W.; Liu, J.; Feng,
G.; Shi, J.; Yan, L.; Liu, H.; He, L.: Significant association between
the genetic variations in the 5-prime end of the N-methyl-D-aspartate
receptor subunit gene GRIN1 and schizophrenia. Biol. Psychiat. 59:
747-753, 2006.
41. Zimmer, M.; Fink, T. M.; Franke, Y.; Lichter, P.; Spiess, J.:
Cloning and structure of the gene encoding the human N-methyl-D-aspartate
receptor (NMDAR1). Gene 159: 219-223, 1995.
*FIELD* CN
Ada Hamosh - updated: 9/23/2011
Ada Hamosh - updated: 8/24/2011
Ada Hamosh - updated: 7/6/2011
Ada Hamosh - updated: 8/17/2010
Ada Hamosh - updated: 1/26/2010
Ada Hamosh - updated: 5/23/2008
Ada Hamosh - updated: 1/24/2008
Ada Hamosh - updated: 12/6/2006
Cassandra L. Kniffin - updated: 11/21/2006
John Logan Black, III - updated: 11/13/2006
Ada Hamosh - updated: 9/8/2006
Ada Hamosh - updated: 1/12/2006
Patricia A. Hartz - updated: 12/7/2005
Ada Hamosh - updated: 11/21/2005
Cassandra L. Kniffin - updated: 9/7/2005
Ada Hamosh - updated: 9/1/2004
John Logan Black, III - updated: 11/12/2003
Cassandra L. Kniffin - updated: 9/24/2003
Ada Hamosh - updated: 4/1/2003
Stylianos E. Antonarakis - updated: 12/2/2002
Ada Hamosh - updated: 11/18/2002
Ada Hamosh - updated: 7/24/2002
Ada Hamosh - updated: 11/20/2000
Ada Hamosh - updated: 8/14/2000
Ada Hamosh - updated: 2/23/2000
Victor A. McKusick - updated: 11/9/1999
Stylianos E. Antonarakis - updated: 9/1/1999
Victor A. McKusick - updated: 2/6/1997
Alan F. Scott - updated: 8/22/1995
*FIELD* CD
Victor A. McKusick: 12/9/1991
*FIELD* ED
carol: 04/12/2013
terry: 7/6/2012
alopez: 9/28/2011
terry: 9/23/2011
alopez: 8/25/2011
terry: 8/24/2011
alopez: 7/7/2011
terry: 7/6/2011
alopez: 8/20/2010
terry: 8/17/2010
alopez: 2/2/2010
terry: 1/26/2010
alopez: 5/29/2008
terry: 5/23/2008
alopez: 2/5/2008
terry: 1/24/2008
alopez: 12/13/2006
terry: 12/6/2006
wwang: 12/1/2006
ckniffin: 11/21/2006
carol: 11/16/2006
terry: 11/13/2006
alopez: 9/19/2006
terry: 9/8/2006
alopez: 1/18/2006
terry: 1/12/2006
wwang: 12/15/2005
wwang: 12/7/2005
alopez: 11/22/2005
terry: 11/21/2005
wwang: 9/28/2005
ckniffin: 9/7/2005
alopez: 9/1/2004
terry: 3/18/2004
carol: 2/27/2004
terry: 11/12/2003
carol: 10/2/2003
ckniffin: 9/24/2003
alopez: 4/1/2003
terry: 4/1/2003
mgross: 12/2/2002
alopez: 11/19/2002
terry: 11/18/2002
cwells: 7/29/2002
terry: 7/24/2002
alopez: 4/30/2002
alopez: 4/17/2002
terry: 4/16/2002
mgross: 11/20/2000
terry: 11/20/2000
alopez: 8/16/2000
terry: 8/14/2000
alopez: 6/8/2000
alopez: 2/24/2000
terry: 2/23/2000
alopez: 11/16/1999
terry: 11/9/1999
psherman: 9/2/1999
mgross: 9/1/1999
alopez: 6/15/1998
psherman: 6/13/1998
psherman: 6/12/1998
jamie: 2/18/1997
terry: 2/6/1997
terry: 2/3/1997
carol: 1/17/1995
carol: 7/19/1993
carol: 3/20/1993
carol: 7/7/1992
supermim: 3/16/1992
*RECORD*
*FIELD* NO
138249
*FIELD* TI
*138249 GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 1; GRIN1
;;N-METHYL-D-ASPARTATE RECEPTOR CHANNEL, SUBUNIT ZETA-1; NMDAR1;;
read moreNR1
*FIELD* TX
CLONING
Glutamate receptors are the predominant excitatory neurotransmitter
receptors in the mammalian brain and are activated in a variety of
normal neurophysiologic processes. The classification of glutamate
receptors is based on their activation by different pharmacologic
agonists. Thus, 1 class, the NMDA receptors, have N-methyl-D-aspartate
as an agonist. Moriyoshi et al. (1991) cloned and characterized a cDNA
encoding the rat NMDA receptor. The protein had a significant sequence
similarity to the AMPA/kainate receptors (see 600282) and contained 4
putative transmembrane segments following a large extracellular domain.
The NMDA receptor mRNA was expressed in neuronal cells throughout the
brain, particularly in the hippocampus, cerebral cortex, and cerebellum.
Kumar et al. (1991) isolated and characterized a protein complex of 4
major proteins that represent an intact complex of the NMDA receptor ion
channel. Furthermore, they cloned the cDNA for one of the subunits of
this receptor complex, the glutamate-binding protein, from rat brain;
see 138251.
Karp et al. (1993) cloned a cDNA encoding the key subunit of the human
NMDA receptor, NMDAR1. It encodes a 938-amino acid protein which showed
high evolutionary conservation in structure and physiologic properties.
The 8 splice variants of vertebrate NR1 have 4 different C-terminal
cytoplasmic tails consisting of different combinations of C-terminal
cassettes, designated C0, C1, C2, and C2-prime. By functional assays and
sequence analysis, Standley et al. (2000) identified an endoplasmic
reticulum (ER) retention signal in the C1 cassette. They also found a
PDZ-interacting domain in the C2-prime cassette that could mask the ER
retention of the C1 cassette and lead to surface expression.
GENE STRUCTURE
Zimmer et al. (1995) cloned the human NMDAR1 gene and showed that it
consists of 21 exons distributed over about 31 kb. Three of the exons
that are alternatively spliced in the rat and which produce 8 isoforms
in that species were also present in the human sequence. The promoter
region contained 2 DNA binding sites for the homeobox proteins
'even-skipped' (see EVX1, 142996 and EVX2, 142991).
MAPPING
Karp et al. (1993) mapped the NMDAR1 gene to 9q34.3 by analysis of blot
hybridization of a DNA panel of human/hamster somatic cell hybrids and
by fluorescence in situ hybridization (FISH). By the same method,
Collins et al. (1993) mapped the NMDAR1 gene to 9q34.3 and Takano et al.
(1993) mapped the gene, which they referred to as the zeta-1 subunit, to
9q34. Collins et al. (1993) and Takano et al. (1993) pointed out that
the gene is a candidate for the site of the mutation in torsion dystonia
(see 128100).
Brett et al. (1994) also mapped the GRIN gene to 9q34.3 by FISH, using a
genomic clone. Cutting a panel of genomic DNAs with 20 restriction
enzymes, they demonstrated a VNTR sequence 5-prime to the gene that was
polymorphic for a number of the enzymes. Using one of these markers for
linkage analysis in the CEPH families, the GRIN1 gene was found to be
linked to D9S7 with a maximum lod score of 20.09 at zero recombination
in males and 0.03% recombination in females.
GENE FUNCTION
Following up on the studies in rodents and nonhuman primates (see later)
that linked the activity of NMDA receptors within the hippocampus to
animals' performance on memory-related tasks, Grunwald et al. (1999)
studied whether hippocampal NMDA receptors, most likely within the CA1
region, participate in human verbal memory processes. They presented
behavioral, anatomic, and electrophysiologic results indicating that
hippocampal NMDA receptors indeed are involved in human memory.
Hardingham et al. (2002) reported that synaptic and extrasynaptic NMDA
receptors have opposite effects on CREB (123810) function, gene
regulation, and neuronal survival. Calcium entry through synaptic NMDA
receptors induced CREB activity and brain-derived neurotrophic factor
(BDNF; 113505) gene expression as strongly as did stimulation of L-type
calcium channels. In contrast, calcium entry through extrasynaptic NMDA
receptors, triggered by bath glutamate exposure or hypoxic/ischemic
conditions, activated a general and dominant CREB shut-off pathway that
blocked induction of BDNF expression. Synaptic NMDA receptors have
antiapoptotic activity, whereas stimulation of extrasynaptic NMDA
receptors caused loss of mitochondrial membrane potential (an early
marker for glutamate-induced neuronal damage) and cell death.
Sin et al. (2002) used in vivo time-lapse imaging of optic tectal cells
in Xenopus laevis tadpoles to demonstrate that enhanced visual activity
driven by a light stimulus promotes dendritic arbor growth. The
stimulus-induced dendritic arbor growth requires glutamate
receptor-mediated synaptic transmission, decreased RhoA (165390)
activity, and increased RAC (see 602048) and CDC42 (116952) activity.
Sin et al. (2002) concluded that their results delineated a role for Rho
GTPases in the structural plasticity driven by visual stimulation in
vivo.
Lee et al. (2002) reported that dopamine D1 receptors (126449) modulate
NMDA glutamate receptor-mediated functions through direct
protein-protein interactions. Two regions in the D1 receptor carboxyl
tail could directly and selectively couple to NMDA glutamate receptor
subunits NR1-1A and NR2A (138253). While one interaction was involved in
the inhibition of NMDA receptor-gated currents, the other was implicated
in the attenuation of NMDA receptor-mediated excitotoxicity through a
phosphatidylinositol 3-kinase (see 171833)-dependent pathway.
Nong et al. (2003) reported that stimulation of the glycine site of the
NMDA receptor initiates signaling through the NMDAR complex, priming the
receptors for clathrin-dependent endocytosis. Glycine binding alone does
not cause the receptor to be endocytosed; this requires both glycine and
glutamate site activation of NMDARs. The priming effect of glycine is
mimicked by the NMDAR glycine site agonist D-serine, and is blocked by
competitive glycine site antagonists. Synaptic as well as extrasynaptic
NMDARs are primed for internalization by glycine site stimulation. Nong
et al. (2003) concluded that their results demonstrated transmembrane
signal transduction through activating the glycine site of NMDARs, and
elucidated a model for modulating cell-cell communication in the central
nervous system.
By examining the kinetics of transmitter binding and channel gating in
single-channel currents from recombinant NR1/NR2A receptors, Popescu et
al. (2004) showed that the synaptic response to trains of impulses is
determined by the molecular reaction mechanism of the receptor. The rate
constants estimated for the activation reaction predicted that, after
binding neurotransmitter, receptors hesitate for approximately 4
milliseconds in a closed high-affinity conformation before they either
proceed towards opening or release neurotransmitter, with about equal
probabilities. Because only about half of the initial fully occupied
receptors become active, repetitive stimulation elicits currents with
distinct waveforms depending on the pulse frequency.
Karadottir et al. (2005) demonstrated that precursor, immature, and
mature oligodendrocytes in the white matter of the cerebellum and corpus
callosum exhibit NMDA-evoked currents, mediated by receptors that are
blocked only weakly by magnesium and that may contain NR1, NR2C
(138254), and NR3 (see 606650) NMDA receptor subunits. NMDA receptors
are present in the myelinating processes of oligodendrocytes, where the
small intracellular space could lead to a large rise in intracellular
ion concentration in response to NMDA receptor activation. Karadottir et
al. (2005) found that simulating ischemia led to development of an
inward current in oligodendrocytes, which was partly mediated by NMDA
receptors.
Salter and Fern (2005) independently showed NMDA receptor subunit
expression on oligodendrocyte processes and the presence of NMDA
receptor subunit mRNA in isolated white matter. NR1, NR2A (138253), NR2B
(138252), NR2C, NR2D, and NR3A subunits showed clustered expression in
cell processes, but NR3B (606651) was absent. During modeled ischemia,
NMDA receptor activation resulted in rapid calcium-dependent detachment
and disintegration of oligodendroglial processes in the white matter of
mice expressing green fluorescent protein (GFP) specifically in
oligodendrocytes. This effect occurred at mouse ages corresponding to
both the initiation and the conclusion of myelination. NR1 subunits were
found mainly in oligodendrocyte processes, whereas AMPA/kainate receptor
subunits (see 600282) were found mainly in the somata. Consistent with
this observation, injury to the somata was prevented by blocking
AMPA/kainate receptors, and preventing injury to oligodendroglial
processes required the blocking of NMDA receptors. Salter and Fern
(2005) suggested that the presence of NMDA receptors in oligodendrocyte
processes may explain why previous studies that focused on the somata
did not detect a role for NMDA receptors in oligodendrocyte injury.
These NMDA receptors bestow a high sensitivity to acute injury.
Tashiro et al. (2006) developed a retrovirus-mediated single-cell gene
knockout technique in mice and showed that the survival of new neurons
is competitively regulated by their own NMDA-type glutamate receptor
during a short, critical period soon after neuronal birth. This finding
indicated that the survival of new neurons and the resulting formation
of new circuits are regulated in an input-dependent, cell-specific
manner. Therefore, Tashiro et al. (2006) suggested that the circuits
formed by new neurons may represent information associated with input
activity within a short time window in the critical period. This
information-specific addition of new circuits through selective survival
or death of new neurons may be a unique attribute of new neurons that
enables them to play a critical role in learning and memory.
Micu et al. (2006) showed that NMDA glutamate receptors mediate calcium
ion accumulation in central myelin in response to chemical ischemia in
vitro. Using 2-photon microscopy, they imaged fluorescence of the
calcium ion indicator X-rhod-1 loaded into oligodendrocytes and the
cytoplasmic compartment of the myelin sheath in adult rat optic nerves.
The AMPA/kainate receptor antagonist NBQX completely blocked the
ischemic calcium ion increase in oligodendroglial cell bodies, but only
modestly reduced the calcium ion increase in myelin. In contrast, the
calcium ion increase in myelin was abolished by broad-spectrum NMDA
receptor antagonists but not by more selective blockers of NR2A and NR2B
subunit-containing receptors. In vitro ischemia causes ultrastructural
damage to both axon cylinders and myelin. NMDA receptor antagonism
greatly reduced the damage to myelin. NR1, NR2, and NR3 subunits were
detected in myelin by immunohistochemistry and immunoprecipitation,
indicating that all necessary subunits were present for the formation of
functional NMDA receptors. Micu et al. (2006) concluded that their data
showed that the mature myelin sheath can respond independently to
injurious stimuli. Given that axons are known to release glutamate, the
finding that the calcium ion increase is mediated in large part by
activation of myelinic NMDA receptors suggested a new mechanism of
axomyelinic signaling.
In mice, Clem et al. (2008) examined the effect of ongoing whisker
stimulation on synaptic strengthening at layer 4-2/3 synapses in the
barrel cortex. Although N-methyl-D-aspartate receptors were required to
initiate strengthening, they subsequently suppressed further
potentiation at these synapses in vitro and in vivo. Despite this
transition, synaptic strengthening continued with additional sensory
activity but instead required the activation of metabotropic glutamate
receptors (see 604473), suggesting a mechanism by which continued
experience can result in increasing synaptic strength over time.
Losonczy et al. (2008) demonstrated that the coupling between local
dendritic spikes and the soma of rat hippocampal CA1 pyramidal neurons
can be modified in a branch-specific manner through an NMDAR-dependent
regulation of dendritic Kv4.2 (605410) potassium channels. These data
suggested that compartmentalized changes in branch excitability could
store multiple complex features of synaptic input, such as their
spatiotemporal correlation. Losonczy et al. (2008) proposed that this
'branch strength potentiation' represents a previously unknown form of
information storage that is distinct from that produced by changes in
synaptic efficacy both at the mechanistic level and in the type of
information stored.
Henneberger et al. (2010) demonstrated that clamping internal calcium
ion in individual CA1 astrocytes of the hippocampus blocks long-term
potentiation (LTP) induction at nearby excitatory synapses by decreasing
the occupancy of the NMDAR coagonist sites by D-serine. This LTP
blockade can be reversed by exogenous D-serine or glycine, whereas
depletion of D-serine or disruption of exocytosis in an individual
astrocyte blocks local LTP. Henneberger et al. (2010) concluded that
calcium ion-dependent release of D-serine from an astrocyte controls
NMDAR-dependent plasticity in many thousands of excitatory synapses
nearby.
Using a self-paced operant task in which mice learn to perform a
particular sequence of actions to obtain an outcome, Jin and Costa
(2010) found neural activity in nigrostriatal circuits specifically
signaling the initiation or the termination of each action sequence.
This start/stop activity emerged during sequence learning, was specific
for particular actions, and did not reflect interval timing, movement
speed, or action value. Furthermore, genetically altering the function
of striatal circuits by developing a nigrostriatal-specific deletion of
the NMDAR1 gene disrupted the development of start/stop activity and
selectively impaired sequence learning. Jin and Costa (2010) concluded
that these results have important implications for understanding the
functional organization of actions and the sequence initiation and
termination impairments observed in basal ganglia disorders.
Attwood et al. (2011) demonstrated in mice that the serine protease
neuropsin (605644) is critical for stress-related plasticity in the
amygdala by regulating the dynamics of the EphB2 (605644)-NMDA receptor
interaction, the expression of Fkbp5 (602623) and anxiety-like behavior.
Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala,
causing dissociation of EphB2 from the NR1 subunit of the NMDA receptor
and promoting membrane turnover of EphB2 receptors. Dynamic EphB2-NR1
interaction enhances NMDA receptor current, induces Fkpb5 gene
expression, and enhances behavioral signatures of anxiety. On stress,
neuropsin-deficient mice do not show EphB2 cleavage and its dissociation
from NR1, resulting in a static EphB2-NR1 interaction, attenuated
induction of the Fkbp5 gene, and low anxiety. The behavioral response to
stress can be restored by intraamygdala injection of neuropsin into
neuropsin-deficient mice and disrupted by the injection of either
anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of
wildtype mice. Attwood et al. (2011) concluded that their findings
established a novel neuronal pathway linking stress-induced proteolysis
of EphB2 in the amygdala to anxiety.
BIOCHEMICAL FEATURES
- Crystal Structure
Furukawa et al. (2005) reported the crystal structure of the
ligand-binding core of NR2A (138253) with glutamate and that of the
NR1-NR2A heterodimer with glutamate and glycine. The NR2A-glutamate
complex defined the determinants of glutamate and NMDA recognition, and
the NR1-NR2A heterodimer suggested a mechanism for ligand-induced ion
channel opening. Analysis of the heterodimer interface, together with
biochemical and electrophysiologic experiments, confirmed that the
NR1-NR2A heterodimer is the functional unit in tetrameric NMDA receptors
and that tyr535 of NR1, located in the subunit interface, modulates the
rate of ion channel deactivation.
Karakas et al. (2011) reported that the GluN1 and GluN2B (138252)
amino-terminal domains forms a heterodimer and that phenylethanolamine
binds at the interface between GluN1 and GluNB2, rather than within the
GluN2B cleft. The crystal structure of the heterodimer formed between
the GluN1b amino-terminal domain from Xenopus laevis and the GluN2B
amino-terminal domain from Rattus norvegicus shows a highly distinct
pattern of subunit arrangement that is different from the arrangements
observed in homodimeric non-NMDA receptors and reveals the molecular
determinants for phenylethanolamine binding. Restriction of domain
movement in the bi-lobed structure of the GluN2B amino-terminal domain,
by engineering of an intersubunit disulfide bond, markedly decreased
sensitivity to ifenprodil, indicating that conformational freedom in the
GluN2B amino-terminal domain is essential for ifenprodil-mediated
allosteric inhibition of NMDA receptors. Karakas et al. (2011) concluded
that their findings paved the way for improving the design of
subtype-specific compounds with therapeutic value for neurologic
disorders and diseases.
MOLECULAR GENETICS
- Association with Schizophrenia Susceptibility
Rice et al. (2001) identified several polymorphisms in the GRIN1 gene,
including a 1001G-C change in the promoter region (dbSNP rs1114620), in
patients with schizophrenia (181500). Begni et al. (2003) investigated
the potential role of the 1001G-C polymorphism in susceptibility to
schizophrenia (181500) in a study of 139 Italian patients with
schizophrenia and 145 healthy control subjects. Sequence analysis
revealed that the C allele may alter the consensus sequence for the
transcription factor NF-kappa-B (164011) and that the frequency of this
allele was higher in patients than in control subjects (p = 0.0085). The
genotype distribution of the C allele was also different, with p =
0.034; if the C allele was considered dominant, the difference was more
significant, p = 0.0137. Begni et al. (2003) concluded that GRIN1 is a
good candidate gene for susceptibility to schizophrenia.
Zhao et al. (2006) genotyped 5 SNPs in GRIN1 in 2,455 schizophrenic and
nonschizophrenic Han Chinese subjects, including population- and
family-based samples, and performed case-control and transmission
disequilibrium test (TDT) analyses. A highly significant association
with schizophrenia was detected at the 5-prime end of GRIN1. Analysis of
single variants and multiple-locus haplotypes indicated that the
association is mainly generated by dbSNP rs11146020 (case-control study:
p = 0.0000013, OR = 0.61, 95% CI = 0.50-0.74; TDT: p = 0.0019, T/NT =
79/123).
- Mental Retardation
Hamdan et al. (2011) identified 2 mutations in GRIN1 resulting in
nonsyndromic intellectual disability (NSID) (MRD8; 614254) as a de novo
event. Both mutations resulted in decreased efficacy of the NMDAR
channel.
ANIMAL MODEL
It has long been hypothesized that memory storage in the mammalian brain
involves modifications of the synaptic connections between neurons. Hebb
(1949) introduced an important principle, known as the Hebb rule, that
of 'correlated activity': when the presynaptic and postsynaptic neurons
are active simultaneously, their connections become strengthened. Tsien
et al. (1996) reviewed reports suggesting that NMDARs can implement the
Hebb rule at the synaptic level and thus are crucial synaptic elements
for the induction of activity-dependent synaptic plasticity. Long-term
potentiation (LTP) is a widely used paradigm for increasing synaptic
efficiency, and its induction requires, in at least one of its forms,
the activation of NMDARs. The hippocampus is the most intensely studied
region for the importance of NMDARs in synaptic plasticity and memory.
Lesions of the hippocampus in humans and other mammals produce severe
amnesia for certain memories. Disruption of NMDARs in hippocampus leads
to blockade of synaptic plasticity and also to memory malfunction. Tsien
et al. (1996) produced a mouse strain in which the deletion of the
Nmdar1 gene was restricted to the CA1 pyramidal cells of the hippocampus
by use of a method that allowed CA1-restricted gene knockout. The mutant
mice grew into adulthood without obvious abnormalities. Adult mice
lacked NMDA receptor-mediated synaptic currents and long term
potentiation in the CA1 synapses and exhibited impaired spatial memory
but unimpaired nonspatial learning. Their results strongly suggested
that activity-dependent modifications of CA1 synapses, mediated by NMDA
receptors, play an essential role in the acquisition of spatial
memories.
In further studies of the CA1-specific Nmdar1 knockout mice, McHugh et
al. (1996) applied multiple electrode recording techniques to freely
behaving mice. They discovered that although the CA1 pyramidal cells of
these mice retain place-related activities, there is a significant
decrease in the spatial specificity of individual place fields. They
also found a striking deficit in the coordinated firing of pairs of
neurons tuned to similar spatial locations. Pairs had uncorrelated
firing even if their fields overlapped.
Rotenberg et al. (1996) studied the effects of an activated form
(CaMKII-Asp286) of Ca(2+)/calmodulin-dependent protein kinase (114078)
in transgenic mice. Normally, spatial location is encoded in the pattern
of firing of individual hippocampal pyramidal cells. When an animal
moves around in a familial environment, different place cells in the
hippocampus fire as the animal enters different regions of space.
Rotenberg et al. (1996) found that the CaMKII-Asp286 transgenic mice
lacked low frequency LTP and did not form stable 'place cells' in the
CA1 region of the hippocampus. Behaviorally, the mice were impaired in
spatial memory tasks.
By insertion of a neomycin resistance gene into intron 20 of the Nmdar1
gene, Mohn et al. (1999) generated mice expressing only 5% of normal
levels of the essential Nmdar1 subunit. Unlike Nmdar1 null mice, these
mice survived to adulthood and displayed behavioral abnormalities,
including increased motor activity and stereotypy and deficits in social
and sexual interactions. These behavioral alterations were similar to
those observed in pharmacologically induced animal models of
schizophrenia and could be ameliorated by treatment with haloperidol or
clozapine, antipsychotic drugs that antagonize dopaminergic and
serotonergic receptors. These findings supported a model in which
reduced NMDA receptor activity results in schizophrenic-like behavior
and revealed how pharmacologic manipulation of monoaminergic pathways
can affect this phenotype.
During et al. (2000) generated a recombinant adeno-associated virus
containing the NMDAR1 subunit and administered this vector orally to
rats. This vaccine generated polyclonal autoantibodies that targeted the
NMDAR1 subunit of the N-methyl-D-aspartate receptor. Transgene
expression persisted for at least 5 months and was associated with a
robust humoral response in the absence of a significant cell-mediated
response. The single-dose vaccine was associated with strong
antiepileptic and neuroprotective activity in rats for both a
kainate-induced seizure model and also a middle cerebral artery
occlusion stroke model at 1 to 5 months following vaccination. During et
al. (2000) concluded that a vaccination strategy targeting brain
proteins is feasible and may have therapeutic potential for neurologic
disorders.
Iwasato et al. (2000) generated mice in which the deletion of the Nmdar1
gene is restricted to excitatory cortical neurons, and demonstrated that
sensory periphery-related patterns develop normally in the brainstem and
thalamic somatosensory relay stations of these mice. In the
somatosensory cortex, thalamocortical afferents corresponding to large
whiskers formed patterns and display critical period plasticity, but
their patterning was not as distinct as that seen in the cortex of
normal mice. Other thalamocortical patterns corresponding to sinus hairs
and digits were mostly absent. The cellular aggregates known as barrels
and barrel boundaries did not develop, even at sites where
thalamocortical afferents cluster. Iwasato et al. (2000) concluded that
cortical NMDARs are essential for the aggregation of layer IV cells into
barrels and for development of the full complement of thalamocortical
patterns.
The hippocampal CA1 region is crucial for converting new memories into
long-term memories, a process believed to continue for weeks after
initial learning. Shimizu et al. (2000) developed an inducible,
reversible, and CA1-specific knockout technique to switch an NMDA
receptor function off or on in CA1 during the consolidation period in
mice. The data indicated that memory consolidation depends on the
reactivation of the NMDA receptor, possibly to reinforce site-specific
synaptic modifications to consolidate memory traces. Shimizu et al.
(2000) suggested that such a synaptic reinforcement process may also
serve as a cellular means by which the new memory is transferred from
the hippocampus to the cortex for permanent storage.
Nakazawa et al. (2002) generated and analyzed a genetically engineered
mouse strain in which the NMDA receptor gene is ablated specifically in
the CA3 pyramidal cells of adult mice. The mutant mice normally acquired
and retrieved spatial reference memory in the Morris water maze, but
they were impaired in retrieving this memory when presented with a
fraction of the original cues. Similarly, hippocampal CA1 pyramidal
cells in mutant mice displayed normal place-related activity in a
full-cue environment but showed a reduction in activity upon partial cue
removal. Nakazawa et al. (2002) concluded that their results provide
direct evidence for CA3 NMDA receptor involvement in associative memory
recall. Nakazawa et al. (2003) found that the mouse strain generated by
Nakazawa et al. (2002) showed impaired rapid acquisition of spatial
memory in the delayed matching-to-place version of the Morris water maze
task in which the animals are tested with novel locations of a hidden
platform. However, the animals were normal in recalling the memory of
familiar platform locations. Compared to control mice, the mutant mice
had larger CA1 place field sizes in novel environments, but not in
familiar environments. The authors concluded that CA3 NMDA receptors
play a role in rapid hippocampal encoding of novel information for the
learning of a one-time experience.
Cui et al. (2004) generated mice in which Nr1 can be temporarily
switched off in the forebrain by doxycycline treatment. Nine months
after conditioned fear training, untreated mice showed normal memory
retention. However, mice with transient inactivation of Nr1 for 30 days
starting at 6 months after initial training had defective memory
retention at 9 months. In subsequent tasks after the 9-month test
period, these mice showed normal learning and memory function. Cui et
al. (2004) suggested that the NMDA receptor is required for the ongoing
preservation of long-term memory storage.
Deng et al. (2006) observed that mice with striatum-specific Nmdar1
knockout using the CRE-loxP system showed impaired motor learning on the
rotarod test compared to wildtype mice. No differences were observed
between the 2 groups in inhibitory avoidance tests thought to involve
the amygdala and hippocampus. In vitro studies of neurons from these
mice showed absence of Nmdar-mediated currents, disruption of dorsal
striatal long-term potentiation, and disruption of ventral striatal
long-term depression. The findings suggested that the striatum is
involved in a subset of motor learning.
*FIELD* AV
.0001
MENTAL RETARDATION, AUTOSOMAL DOMINANT 8
GRIN1, GLU662LYS
In a 10-year-old female with moderate mental retardation (MRD8; 614254),
Hamdan et al. (2011) identified a heterozygous G-to-A transition at
nucleotide 1984 of the GRIN1 gene, resulting in a glu-to-lys
substitution at codon 662 (E662K). The mutation occurred de novo. The
patient had a normal neural exam and normal brain imaging by CT scan,
and there was no evidence of epilepsy. Functional studies in Xenopus
oocytes showed that this mutation produced a significant increase in
NMDAR-induced calcium currents; excessive calcium influx through NMDAR
could lead to excitotoxic neuronal cell damage. This mutation was not
identified in 285 healthy controls.
.0002
MENTAL RETARDATION, AUTOSOMAL DOMINANT 8
GRIN1, 3-BP DUP, SER560
In a 7.5-year-old boy with severe mental retardation (MRD8; 614254),
Hamdan et al. (2011) identified a duplication of 3 nucleotides between
positions 1679 and 1681 in the GRIN1 cDNA (1679_1681dup), resulting in
duplication of serine at codon 560 (ser560dup). The mutation was
identified de novo in the patient and was not seen in 285 control
chromosomes. The patient had partial complex seizures, hypotonia, and
normal brain imaging by MRI. Functional studies showed near abolition of
the activity of the NMDA receptor in Xenopus oocytes. The duplication at
codon 560 altered the 3-dimensional structure at the receptor's channel
pore entrance.
*FIELD* RF
1. Attwood, B. K.; Bourgognon, J.-M.; Patel, S.; Mucha, M.; Schiavon,
E.; Skrzypiec, A. E.; Young, K. W.; Shiosaka, S.; Korostynski, M.;
Piechota, M.; Przewlocki, R.; Pawlak, R.: Neuropsin cleaves EphB2
in the amygdala to control anxiety. Nature 473: 372-375, 2011.
2. Begni, S.; Moraschi, S.; Bignotti, S.; Fumagalli, F.; Rillosi,
L.; Perez, J.; Gennarelli, M.: Association between the G1001C polymorphism
in the GRIN1 gene promoter region and schizophrenia. Biol. Psychiat. 53:
617-619, 2003.
3. Brett, P. M.; Le Bourdelles, B.; See, C. G.; Whiting, P. J.; Attwood,
J.; Woodward, K.; Robertson, M. M.; Kalsi, G.; Povey, S.; Gurling,
H. M. D.: Genomic cloning and localization by FISH and linkage analysis
of the human gene encoding the primary subunit NMDAR1 (GRIN1) of the
NMDA receptor channel. Ann. Hum. Genet. 58: 95-100, 1994.
4. Clem, R. L.; Celikel, T.; Barth, A. L.: Ongoing in vivo experience
triggers synaptic metaplasticity in the neocortex. Science 319:
101-104, 2008.
5. Collins, C.; Duff, C.; Duncan, A. M. V.; Planells-Cases, R.; Sun,
W.; Norremolle, A.; Michaelis, E.; Montal, M.; Worton, R.; Hayden,
M. R.: Mapping of the human NMDA receptor subunit (NMDAR1) and the
proposed NMDA receptor glutamate-binding subunit (NMDARA1) to chromosomes
9q34.3 and chromosome 8, respectively. Genomics 17: 237-239, 1993.
6. Cui, Z.; Wang, H.; Tan, Y.; Zaia, K. A.; Zhang, S.; Tsien, J. Z.
: Inducible and reversible NR1 knockout reveals crucial role of the
NMDA receptor in preserving remote memories in the brain. Neuron 41:
781-793, 2004.
7. Deng, M. T.; Yokoi, F.; Yin, H. H.; Lovinger, D. M.; Wang, Y.;
Li, Y.: Disrupted motor learning and long-term synaptic plasticity
in mice lacking NMDAR1 in the striatum. Proc. Nat. Acad. Sci. 103:
15254-15259, 2006.
8. During, M. J.; Symes, C. W.; Lawlor, P. A.; Lin, J.; Dunning, J.;
Fitzsimons, H. L.; Poulsen, D.; Leone, P.; Xu, R.; Dicker, B. L.;
Lipski, J.; Young, D.: An oral vaccine against NMDAR1 with efficacy
in experimental stroke and epilepsy. Science 287: 1453-1460, 2000.
9. Furukawa, H.; Singh, S. K.; Mancusso, R.; Gouaux, E.: Subunit
arrangement and function in NMDA receptors. Nature 438: 185-192,
2005.
10. Grunwald, T.; Beck, H.; Lehnertz, K.; Blumcke, I.; Pezer, N.;
Kurthen, M.; Fernandez, G.; Van Roost, D.; Heinze, H. J.; Kutas, M.;
Elger, C. E.: Evidence relating human verbal memory to hippocampal
N-methyl-D-aspartate receptors. Proc. Nat. Acad. Sci. 96: 12085-12089,
1999.
11. Hamdan, F. F.; Gauthier, J.; Araki, Y.; Lin, D.-T.; Yoshizawa,
Y.; Higashi, K.; Park, A.-R.; Spiegelman, D.; Dobrzeniecka, S.; Piton,
A.; Tomitori, H.; Daoud, H.; and 22 others: Excess of de novo deleterious
mutations in genes associated with glutamatergic systems in nonsyndromic
intellectual disability. Am. J. Hum. Genet. 88: 306-316, 2011. Note:
Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.
12. Hardingham, G. E.; Fukunaga, Y.; Bading, H.: Extrasynaptic NMDARs
oppose synaptic NMDARs by triggering CREB shut-off and cell death
pathways. Nature Neurosci. 5: 405-414, 2002.
13. Hebb, D. O.: The Organization of Behavior: A Neuropsychological
Theory. New York: John Wiley , 1949.
14. Henneberger, C.; Papouin, T.; Oliet, S. H. R.; Rusakov, D. A.
: Long-term potentiation depends on release of D-serine from astrocytes. Nature 463:
232-236, 2010.
15. Iwasato, T.; Datwani, A.; Wolf, A. M.; Nishiyama, H.; Taguchi,
Y.; Tonegawa, S.; Knopfel, T.; Erzurumlu, R. S.; Itohara, S.: Cortex-restricted
disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 406:
726-731, 2000.
16. Jin, X.; Costa, R. M.: Start/stop signals emerge in nigrostriatal
circuits during sequence learning. Nature 466: 457-462, 2010.
17. Karadottir, R.; Cavelier, P.; Bergersen, L. H.; Attwell, D.:
NMDA receptors are expressed in oligodendrocytes and activated in
ischaemia. Nature 438: 1162-1166, 2005.
18. Karakas, E.; Simorowski, N.; Furukawa, H.: Subunit arrangement
and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. Nature 475:
249-253, 2011.
19. Karp, S. J.; Masu, M.; Eki, T.; Ozawa, K.; Nakanishi, S.: Molecular
cloning and chromosomal localization of the key subunit of the human
N-methyl-D-aspartate receptor. J. Biol. Chem. 268: 3728-3733, 1993.
20. Kumar, K. N.; Tilakaratne, N.; Johnson, P. S.; Allen, A. E.; Michaelis,
E. K.: Cloning of cDNA for the glutamate-binding subunit of an NMDA
receptor complex. Nature 354: 70-73, 1991.
21. Lee, F. J. S.; Xue, S.; Pei, L.; Vukusic, B.; Chery, N.; Wang,
Y.; Wang, Y. T.; Niznik, H. B.; Yu, X.; Liu, F.: Dual recognition
of NMDA receptor functions by direct protein-protein interactions
with the dopamine D1 receptor. Cell 111: 219-230, 2002.
22. Losonczy, A.; Makara, J. K.; Magee, J. C.: Compartmentalized
dendritic plasticity and input feature storage in neurons. Nature 452:
436-441, 2008.
23. McHugh, T. J.; Blum, K. I.; Tsien, J. Z.; Tonegawa, S.; Wilson,
M. A.: Impaired hippocampal representation of space in CA1-specific
NMDAR1 knockout mice. Cell 87: 1339-1349, 1996.
24. Micu, I.; Jiang, Q.; Coderre, E.; Ridsdale, A.; Zhang, L.; Woulfe,
J.; Yin, X.; Trapp, B. D.; McRory, J. E.; Rehak, R.; Zamponi, G. W.;
Wang, W.; Stys, P. K.: NMDA receptors mediate calcium accumulation
in myelin during chemical ischaemia. Nature 439: 988-992, 2006.
25. Mohn, A. R.; Gainetdinov, R. R.; Caron, M. G.; Koller, B. H.:
Mice with reduced NMDA receptor expression display behaviors related
to schizophrenia. Cell 98: 427-436, 1999.
26. Moriyoshi, K.; Masu, M.; Ishii, T.; Shigemoto, R.; Mizuno, N.;
Nakanishi, S.: Molecular cloning and characterization of the rat
NMDA receptor. Nature 354: 31-37, 1991.
27. Nakazawa, K.; Quirk, M. C.; Chitwood, R. A.; Watanabe, M.; Yeckel,
M. F.; Sun, L. D.; Kato, A.; Carr, C. A.; Johnston, D.; Wilson, M.
A.; Tonegawa, S.: Requirement for hippocampal CA3 NMDA receptors
in associative memory recall. Science 297: 211-218, 2002.
28. Nakazawa, K.; Sun, L. D.; Quirk, M. C.; Rondi-Reig, L.; Wilson,
M. A.; Tonegawa, S.: Hippocampal CA3 NMDA receptors are crucial for
memory acquisition of one-time experience. Neuron 38: 305-315, 2003.
29. Nong, Y.; Huang, Y.-Q.; Ju, W.; Kalia, L. V.; Ahmadian, G.; Wang,
Y. T.; Salter, M. W.: Glycine binding primes NMDA receptor internalization. Nature 422:
302-307, 2003.
30. Popescu, G.; Robert, A.; Howe, J. R.; Auerbach, A.: Reaction
mechanism determines NMDA receptor response to repetitive stimulation. Nature 430:
790-793, 2004.
31. Rice, S. R.; Niu, N.; Berman, D. B.; Heston, L. L.; Sobell, J.
L.: Identification of single nucleotide polymorphisms (SNPs) and
other sequence changes and estimation of nucleotide diversity in coding
and flanking regions of the NMDAR1 receptor gene in schizophrenic
patients. Molec. Psychiat. 6: 274-284, 2001.
32. Rotenberg, A.; Mayford, M.; Hawkins, R. D.; Kandel, E. R.; Muller,
R. U.: Mice expressing activated CaMKII lack low frequency LTP and
do not form stable place cells in the CA1 region of the hippocampus. Cell 87:
1351-1361, 1996.
33. Salter, M. G.; Fern, R.: NMDA receptors are expressed in developing
oligodendrocyte processes and mediate injury. Nature 438: 1167-1171,
2005.
34. Shimizu, E.; Tang, Y.-P.; Rampon, C.; Tsien, J. Z.: NMDA receptor-dependent
synaptic reinforcement as a crucial process for memory consolidation. Science 290:
1170-1174, 2000. Note: Erratum: Science 291: 1902 only, 2001.
35. Sin, W. C.; Haas, K.; Ruthazer, E. S.; Cline, H. T.: Dendrite
growth increased by visual activity requires NMDA receptor and Rho
GTPases. Nature 419: 475-480, 2002.
36. Standley, S.; Roche, K. W.; McCallum, J.; Sans, N.; Wenthold,
R. J.: PDZ domain suppression of an ER retention signal in NMDA receptor
NR1 splice variants. Neuron 28: 887-898, 2000.
37. Takano, H.; Onodera, O.; Tanaka, H.; Mori, H.; Sakimura, K.; Hori,
T.; Kobayashi, H.; Mishina, M.; Tsuji, S.: Chromosomal localization
of the epsilon-1, epsilon-3, and zeta-1 subunit genes of the human
NMDA receptor channel. Biochem. Biophys. Res. Commun. 197: 922-926,
1993.
38. Tashiro, A.; Sandler, V. M.; Toni, N.; Zhao, C.; Gage, F. H.:
NMDA-receptor-mediated, cell-specific integration of new neurons in
adult dentate gyrus. Nature 442: 929-933, 2006.
39. Tsien, J. Z.; Huerta, P. T.; Tonegawa, S.: The essential role
of hippocampal CA1 NMDA-receptor-dependent synaptic plasticity in
spatial memory. Cell 87: 1327-1338, 1996.
40. Zhao, X.; Li, H.; Shi, Y.; Tang, R.; Chen, W.; Liu, J.; Feng,
G.; Shi, J.; Yan, L.; Liu, H.; He, L.: Significant association between
the genetic variations in the 5-prime end of the N-methyl-D-aspartate
receptor subunit gene GRIN1 and schizophrenia. Biol. Psychiat. 59:
747-753, 2006.
41. Zimmer, M.; Fink, T. M.; Franke, Y.; Lichter, P.; Spiess, J.:
Cloning and structure of the gene encoding the human N-methyl-D-aspartate
receptor (NMDAR1). Gene 159: 219-223, 1995.
*FIELD* CN
Ada Hamosh - updated: 9/23/2011
Ada Hamosh - updated: 8/24/2011
Ada Hamosh - updated: 7/6/2011
Ada Hamosh - updated: 8/17/2010
Ada Hamosh - updated: 1/26/2010
Ada Hamosh - updated: 5/23/2008
Ada Hamosh - updated: 1/24/2008
Ada Hamosh - updated: 12/6/2006
Cassandra L. Kniffin - updated: 11/21/2006
John Logan Black, III - updated: 11/13/2006
Ada Hamosh - updated: 9/8/2006
Ada Hamosh - updated: 1/12/2006
Patricia A. Hartz - updated: 12/7/2005
Ada Hamosh - updated: 11/21/2005
Cassandra L. Kniffin - updated: 9/7/2005
Ada Hamosh - updated: 9/1/2004
John Logan Black, III - updated: 11/12/2003
Cassandra L. Kniffin - updated: 9/24/2003
Ada Hamosh - updated: 4/1/2003
Stylianos E. Antonarakis - updated: 12/2/2002
Ada Hamosh - updated: 11/18/2002
Ada Hamosh - updated: 7/24/2002
Ada Hamosh - updated: 11/20/2000
Ada Hamosh - updated: 8/14/2000
Ada Hamosh - updated: 2/23/2000
Victor A. McKusick - updated: 11/9/1999
Stylianos E. Antonarakis - updated: 9/1/1999
Victor A. McKusick - updated: 2/6/1997
Alan F. Scott - updated: 8/22/1995
*FIELD* CD
Victor A. McKusick: 12/9/1991
*FIELD* ED
carol: 04/12/2013
terry: 7/6/2012
alopez: 9/28/2011
terry: 9/23/2011
alopez: 8/25/2011
terry: 8/24/2011
alopez: 7/7/2011
terry: 7/6/2011
alopez: 8/20/2010
terry: 8/17/2010
alopez: 2/2/2010
terry: 1/26/2010
alopez: 5/29/2008
terry: 5/23/2008
alopez: 2/5/2008
terry: 1/24/2008
alopez: 12/13/2006
terry: 12/6/2006
wwang: 12/1/2006
ckniffin: 11/21/2006
carol: 11/16/2006
terry: 11/13/2006
alopez: 9/19/2006
terry: 9/8/2006
alopez: 1/18/2006
terry: 1/12/2006
wwang: 12/15/2005
wwang: 12/7/2005
alopez: 11/22/2005
terry: 11/21/2005
wwang: 9/28/2005
ckniffin: 9/7/2005
alopez: 9/1/2004
terry: 3/18/2004
carol: 2/27/2004
terry: 11/12/2003
carol: 10/2/2003
ckniffin: 9/24/2003
alopez: 4/1/2003
terry: 4/1/2003
mgross: 12/2/2002
alopez: 11/19/2002
terry: 11/18/2002
cwells: 7/29/2002
terry: 7/24/2002
alopez: 4/30/2002
alopez: 4/17/2002
terry: 4/16/2002
mgross: 11/20/2000
terry: 11/20/2000
alopez: 8/16/2000
terry: 8/14/2000
alopez: 6/8/2000
alopez: 2/24/2000
terry: 2/23/2000
alopez: 11/16/1999
terry: 11/9/1999
psherman: 9/2/1999
mgross: 9/1/1999
alopez: 6/15/1998
psherman: 6/13/1998
psherman: 6/12/1998
jamie: 2/18/1997
terry: 2/6/1997
terry: 2/3/1997
carol: 1/17/1995
carol: 7/19/1993
carol: 3/20/1993
carol: 7/7/1992
supermim: 3/16/1992
MIM
614254
*RECORD*
*FIELD* NO
614254
*FIELD* TI
#614254 MENTAL RETARDATION, AUTOSOMAL DOMINANT 8; MRD8
*FIELD* TX
A number sign (#) is used with this entry because this form of mental
read moreretardation is caused by heterozygous mutation in the GRIN1 gene
(138249) on chromosome 9q34.3.
CLINICAL FEATURES
Hamdan et al. (2011) hypothesized that de novo mutations in synaptic
genes explain an important fraction of sporadic nonsyndromic
intellectual disability (NSID) cases. They sequenced 197 genes encoding
glutamate receptors and a large subset of their interacting proteins in
95 sporadic cases of NSID. They found 2 patients with mutations in the
GRIN1 gene. The first was a 10-year-old girl with moderate mental
retardation. There was no evidence of epilepsy, and she had a normal
neurologic exam and CT scan. Brain MRI was not performed. The second
patient was a 7.5-year-old male with severe mental retardation, partial
complex seizures, hypotonia, and normal brain MRI; a CT scan was not
performed. Both cases were sporadic.
MOLECULAR GENETICS
In a 10-year-old girl with moderate mental retardation, Hamdan et al.
(2011) identified a missense mutation in the GRIN1 gene (E662K;
138249.0001). In a 7.5-year-old boy with severe mental retardation and
seizures, they detected an in-frame duplication of serine at GRIN1 codon
560 (138249.0002). Both mutations occurred de novo. The E662K mutation
resulted in increased calcium currents, and there was no effect of
receptor affinity on the agonist glycine or its response to magnesium
blockade. The ser560dup mutation resulted in loss of activity of the
receptor, and structural analysis showed significant change in the
3-dimensional structure at the receptor's channel pore entrance.
*FIELD* RF
1. Hamdan, F. F.; Gauthier, J.; Araki, Y.; Lin, D.-T.; Yoshizawa,
Y.; Higashi, K.; Park, A.-R.; Spiegelman, D.; Dobrzeniecka, S.; Piton,
A.; Tomitori, H.; Daoud, H.; and 22 others: Excess of de novo deleterious
mutations in genes associated with glutamatergic systems in nonsyndromic
intellectual disability. Am. J. Hum. Genet. 88: 306-316, 2011. Note:
Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.
*FIELD* CD
Ada Hamosh: 9/28/2011
*FIELD* ED
terry: 07/06/2012
alopez: 11/2/2011
alopez: 9/28/2011
*RECORD*
*FIELD* NO
614254
*FIELD* TI
#614254 MENTAL RETARDATION, AUTOSOMAL DOMINANT 8; MRD8
*FIELD* TX
A number sign (#) is used with this entry because this form of mental
read moreretardation is caused by heterozygous mutation in the GRIN1 gene
(138249) on chromosome 9q34.3.
CLINICAL FEATURES
Hamdan et al. (2011) hypothesized that de novo mutations in synaptic
genes explain an important fraction of sporadic nonsyndromic
intellectual disability (NSID) cases. They sequenced 197 genes encoding
glutamate receptors and a large subset of their interacting proteins in
95 sporadic cases of NSID. They found 2 patients with mutations in the
GRIN1 gene. The first was a 10-year-old girl with moderate mental
retardation. There was no evidence of epilepsy, and she had a normal
neurologic exam and CT scan. Brain MRI was not performed. The second
patient was a 7.5-year-old male with severe mental retardation, partial
complex seizures, hypotonia, and normal brain MRI; a CT scan was not
performed. Both cases were sporadic.
MOLECULAR GENETICS
In a 10-year-old girl with moderate mental retardation, Hamdan et al.
(2011) identified a missense mutation in the GRIN1 gene (E662K;
138249.0001). In a 7.5-year-old boy with severe mental retardation and
seizures, they detected an in-frame duplication of serine at GRIN1 codon
560 (138249.0002). Both mutations occurred de novo. The E662K mutation
resulted in increased calcium currents, and there was no effect of
receptor affinity on the agonist glycine or its response to magnesium
blockade. The ser560dup mutation resulted in loss of activity of the
receptor, and structural analysis showed significant change in the
3-dimensional structure at the receptor's channel pore entrance.
*FIELD* RF
1. Hamdan, F. F.; Gauthier, J.; Araki, Y.; Lin, D.-T.; Yoshizawa,
Y.; Higashi, K.; Park, A.-R.; Spiegelman, D.; Dobrzeniecka, S.; Piton,
A.; Tomitori, H.; Daoud, H.; and 22 others: Excess of de novo deleterious
mutations in genes associated with glutamatergic systems in nonsyndromic
intellectual disability. Am. J. Hum. Genet. 88: 306-316, 2011. Note:
Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.
*FIELD* CD
Ada Hamosh: 9/28/2011
*FIELD* ED
terry: 07/06/2012
alopez: 11/2/2011
alopez: 9/28/2011