GRID2

Summary

GRID2 (glutamate ionotropic receptor delta type subunit 2, HGNC:4576) is a protein-coding gene on chromosome 4q22.1-q22.2, encoding Glutamate receptor ionotropic, delta-2 (O43424). Member of the ionotropic glutamate receptor family, which plays a crucial role in synaptic organization and signal transduction in the central nervous system.

The protein encoded by this gene is a member of the family of ionotropic glutamate receptors which are the predominant excitatory neurotransmitter receptors in the mammalian brain. The encoded protein is a multi-pass membrane protein that is expressed selectively in cerebellar Purkinje cells. A point mutation in the mouse ortholog, associated with the phenotype named ’lurcher’, in the heterozygous state leads to ataxia resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development. Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis. This protein also plays a role in synapse organization between parallel fibers and Purkinje cells. Alternate splicing results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause cerebellar ataxia in humans.

Source: NCBI Gene 2895 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive spinocerebellar ataxia 18 (Strong, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 364 total — 15 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes
• MANE Select transcript: NM_001510

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4576
Approved symbol	GRID2
Name	glutamate ionotropic receptor delta type subunit 2
Location	4q22.1-q22.2
Locus type	gene with protein product
Status	Approved
Aliases	GluD2, GluR-delta-2
Ensembl gene	ENSG00000152208
Ensembl biotype	protein_coding
OMIM	602368
Entrez	2895

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000282020, ENST00000502699, ENST00000505687, ENST00000510992, ENST00000512631, ENST00000513976, ENST00000515744, ENST00000611049, ENST00000637838

RefSeq mRNA: 2 — MANE Select: NM_001510 NM_001286838, NM_001510

CCDS: CCDS3637, CCDS68758

Canonical transcript exons

ENST00000282020 — 16 exons

Exon	Start	End
ENSE00001003968	93395607	93395708
ENSE00001003971	93490639	93490777
ENSE00001003973	93422771	93422968
ENSE00001003974	93455662	93455974
ENSE00001003976	93224614	93224775
ENSE00001071553	93238371	93238490
ENSE00001289828	93626269	93626435
ENSE00001314676	93769210	93769450
ENSE00001329269	93515216	93515411
ENSE00001329292	93772076	93774566
ENSE00002056780	92303966	92304744
ENSE00003535928	93207404	93207457
ENSE00003564045	93084995	93085279
ENSE00003589982	93110748	93110953
ENSE00003613638	92590131	92590286
ENSE00003676547	93216738	93216911

Expression profiles

Bgee: expression breadth ubiquitous, 114 present calls, max score 92.91.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3495 / max 347.8903, expressed in 267 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48875	1.0696	190
48881	0.5163	132
48877	0.3109	114
48882	0.1576	69
48876	0.1108	63
48883	0.0648	25
48880	0.0402	5
48878	0.0364	14
48874	0.0261	7
48879	0.0149	5

Top tissues by expression

260 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	92.91	gold quality
left testis	UBERON:0004533	92.57	gold quality
testis	UBERON:0000473	87.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.09	gold quality
right hemisphere of cerebellum	UBERON:0014890	79.70	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.50	gold quality
cerebellar cortex	UBERON:0002129	79.08	gold quality
cerebellar hemisphere	UBERON:0002245	78.95	gold quality
ventricular zone	UBERON:0003053	78.50	gold quality
cerebellum	UBERON:0002037	77.25	gold quality
cortical plate	UBERON:0005343	75.68	gold quality
ganglionic eminence	UBERON:0004023	73.56	gold quality
corpus callosum	UBERON:0002336	69.23	gold quality
nucleus accumbens	UBERON:0001882	68.49	gold quality
prefrontal cortex	UBERON:0000451	67.47	gold quality
caudate nucleus	UBERON:0001873	66.59	gold quality
hypothalamus	UBERON:0001898	65.65	gold quality
putamen	UBERON:0001874	65.64	gold quality
anterior cingulate cortex	UBERON:0009835	64.81	gold quality
cingulate cortex	UBERON:0003027	64.74	gold quality
sural nerve	UBERON:0015488	64.68	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	64.48	gold quality
embryo	UBERON:0000922	63.68	gold quality
amygdala	UBERON:0001876	62.32	gold quality
spinal cord	UBERON:0002240	62.20	gold quality
right adrenal gland cortex	UBERON:0035827	61.48	gold quality
Brodmann (1909) area 9	UBERON:0013540	61.38	gold quality
neocortex	UBERON:0001950	60.64	gold quality
buccal mucosa cell	CL:0002336	60.23	gold quality
right adrenal gland	UBERON:0001233	59.75	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	1054.09
E-HCAD-35	yes	84.50
E-HCAD-25	yes	23.70
E-ANND-3	yes	7.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

266 targeting GRID2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6127	100.00	66.76	2188
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-32-5P	99.98	75.21	1964

Literature-anchored findings (GeneRIF, showing 16)

• Thus, phosphorylation of -2T and/or -1S of GluRdelta2 C-terminus by PKA may regulate the binding of GluRdelta2 to its scaffolding protein, Delphilin. (PMID:17027646)
• The carboxy terminus of transgenic GluRdelta2 conveys the signal(s) necessary for long-term depression induction and motor learning. (PMID:18256267)
• Glutamate receptor delta2 is involved in a common mechanism that restricts the number of synaptic AMPA receptors at parallel fiber synapses in cerebellar Purkinje cells. (PMID:21368048)
• Tests for gene-environment interaction between these 33 genes and maternal smoking found evidence for interaction with two additional genes: GRID2 and ELAVL2 among European mothers (PMID:23512105)
• GRID2 mutations are associated with a recessive syndrome causing cerebellar ataxia and eye movement abnormalities. (PMID:24078737)
• GluD2 gating is triggered by type 1 metabotropic glutamate receptors. (PMID:24357660)
• We demonstrated for the first time GRID2 expression and localization in human and murine retina, providing evidence for a novel functional role of GRID2 in the retina. (PMID:25122145)
• findings suggest a possible role of GRID2 in the susceptibility to develop mevalonate kinase deficiency. GRID2 gene associated with MKD: The rs1450500 SNP was differently distributed in patients with MKD with respect to those with recurrent fever. (PMID:25146332)
• GRID2 point mutations: cerebellar ataxia is the core phenotype, but with variable severity ranging from very mild adult-onset to congenital-onset linked to both the heterozygous and homozygous state of the variant, and the position of the mutation. (PMID:25841024)
• Glutamate system genes including have been associated with disease risk in recent analyses from the Psychiatric Genomics Consortium. (PMID:26905411)
• GRID2 gene can be a suppressor in TNF-induced neurodegeneration which may help to understand the main factors leading to autism. (PMID:27019035)
• Report on a consanguineous family with autosomal recessive childhood onset of cerebellar ataxia and delayed psychomotor development. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein. (PMID:29207948)
• Association of Gene Variations in Ionotropic Glutamate Receptor and Attention-Deficit/Hyperactivity Disorder in the Chinese Population: A Two-Stage Case-Control Study. (PMID:32065002)
• Autosomal recessive spinocerebellar ataxia 18 caused by homozygous exon 14 duplication in GRID2 and review of the literature. (PMID:32170608)
• Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect. (PMID:35159210)
• Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants. (PMID:37944084)

Cross-species orthologs

35 orthologs

Organism	Symbol	Gene ID
danio_rerio	grid2	ENSDARG00000055302
mus_musculus	Grid2	ENSMUSG00000071424
rattus_norvegicus	Grid2	ENSRNOG00000006174
drosophila_melanogaster	GluRIIA	FBGN0004620
drosophila_melanogaster	GluRIIB	FBGN0020429
drosophila_melanogaster	clumsy	FBGN0026255
drosophila_melanogaster	GluRIID	FBGN0028422
drosophila_melanogaster	Ir7b	FBGN0029965
drosophila_melanogaster	Ir7c	FBGN0029966
drosophila_melanogaster	Ir7g	FBGN0029968
drosophila_melanogaster	Ir25a	FBGN0031634
drosophila_melanogaster	Ir60a	FBGN0034994
drosophila_melanogaster	Ir64a	FBGN0035604
drosophila_melanogaster	Ir68a	FBGN0036150
drosophila_melanogaster	Ir75a	FBGN0036757
drosophila_melanogaster	Ir75d	FBGN0036829
drosophila_melanogaster	Ir76b	FBGN0036937
drosophila_melanogaster	Ir84a	FBGN0037501
drosophila_melanogaster	Ir85a	FBGN0037630
drosophila_melanogaster	Ir92a	FBGN0038789
drosophila_melanogaster	Grik	FBGN0038840
drosophila_melanogaster	Ir41a	FBGN0040849
drosophila_melanogaster	GluRIIC	FBGN0046113
drosophila_melanogaster	GluRIIE	FBGN0051201
drosophila_melanogaster	Nmdar2	FBGN0053513
drosophila_melanogaster	Ir7e	FBGN0259189
drosophila_melanogaster	Ir94d	FBGN0259193
drosophila_melanogaster	Ir93a	FBGN0259215
drosophila_melanogaster	Ir40a	FBGN0259683
drosophila_melanogaster	Ir76a	FBGN0260874
drosophila_melanogaster	Ir75c	FBGN0261401
drosophila_melanogaster	Ir75b	FBGN0261402
caenorhabditis_elegans		WBGENE00001618
caenorhabditis_elegans		WBGENE00003775
caenorhabditis_elegans		WBGENE00012190

Paralogs (17): GRIN2D (ENSG00000105464), GRIK5 (ENSG00000105737), GRIN3B (ENSG00000116032), GRIA2 (ENSG00000120251), GRIA3 (ENSG00000125675), GRIK4 (ENSG00000149403), GRIA4 (ENSG00000152578), GRIA1 (ENSG00000155511), GRIN2C (ENSG00000161509), GRIK3 (ENSG00000163873), GRIK2 (ENSG00000164418), GRIK1 (ENSG00000171189), GRIN1 (ENSG00000176884), GRID1 (ENSG00000182771), GRIN2A (ENSG00000183454), GRIN3A (ENSG00000198785), GRIN2B (ENSG00000273079)

Protein

Protein identifiers

Glutamate receptor ionotropic, delta-2 — O43424 (reviewed: O43424)

All UniProt accessions (5): O43424, A0A087X043, A0A1B0GW49, D6R976, D6R9W8

UniProt curated annotations — full annotation on UniProt →

Function. Member of the ionotropic glutamate receptor family, which plays a crucial role in synaptic organization and signal transduction in the central nervous system. Although it shares structural features with ionotropic glutamate receptors, does not bind glutamate as a primary ligand. Promotes synaptogenesis and mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses through the NRX1B-CBLN1-GRID2 triad complex. In the presence of neurexins and cerebellins, forms cation-selective channels that are proposed to be gated by glycine and D-serine. However, recent research disputes this ligand-gated cation channel activity. Cation-selective ion channel activity can be triggered by GRM1 in Purkinje cells.

Subunit / interactions. Tetramer; dimer of dimers. Interacts with EML2, MAGI2 (via PDZ domains) and AP4M1. Interacts with BECN1, GOPC, GRID2IP, SHANK1 and SHANK2. Interacts with CBLN2, but not with CBLN4. Interacts with CBLN1 (via C1q domain); the interaction is CBLN1-NRX1 complex formation-dependent; CBLN1-binding is calcium-independent; CBLN1 hexamers anchor GRID2 N-terminal domain dimers to monomeric NRXN1 isoform beta; promotes synaptogenesis and mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis.

Subcellular location. Postsynaptic cell membrane.

Disease relevance. Spinocerebellar ataxia, autosomal recessive, 18 (SCAR18) [MIM:616204] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR18 features include progressive cerebellar atrophy, delayed psychomotor development, severely impaired gait, ocular movement abnormalities, and intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PDZ-binding motif mediates interaction with GOPC.

Similarity. Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRID2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O43424-1	1	yes
O43424-2	2

RefSeq proteins (2): NP_001273767, NP_001501* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001320	Iontro_rcpt_C	Domain
IPR001508	Iono_Glu_rcpt_met	Family
IPR001828	ANF_lig-bd_rcpt	Domain
IPR015683	Ionotropic_Glu_rcpt	Family
IPR019594	Glu/Gly-bd	Domain
IPR028082	Peripla_BP_I	Homologous_superfamily

Pfam: PF00060, PF01094, PF10613

Catalyzed reactions (Rhea), 2 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (96 total): mutagenesis site 18, strand 18, helix 15, sequence variant 7, binding site 6, sequence conflict 6, modified residue 4, topological domain 4, glycosylation site 4, disulfide bond 3, transmembrane region 3, region of interest 2, signal peptide 1, chain 1, short sequence motif 1, site 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
5KC8	X-RAY DIFFRACTION	1.75
5KCA	X-RAY DIFFRACTION	3.1
9NWO	ELECTRON MICROSCOPY	3.57
9OOO	ELECTRON MICROSCOPY	3.68
9NWP	ELECTRON MICROSCOPY	3.69
9NWQ	ELECTRON MICROSCOPY	3.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43424-F1	76.07	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 76 (essential for dimerization)

Ligand- & substrate-binding residues (6): 531; 534; 535; 753; 755; 757

Post-translational modifications (4): 883, 886, 890, 1006

Disulfide bonds (3): 83–355, 99–131, 298–310

Glycosylation sites (4): 293, 426, 713, 716

Mutagenesis-validated functional residues (18):

Position	Phenotype
24	reduces binding to cbln1; when associated with d76. abolishes cbln1 binding; when associated with a-26; a-61; d-76 and a
25	reduces binding to cbln1; when associated with d76.
26	reduces binding to cbln1; when associated with d76. abolishes cbln1 binding; when associated with a-24; a-61; d-76 and a
60	no effect on cbln1 interaction; when associated with d76.
61	reduces binding to cbln1; when associated with d76. abolishes cbln1 binding; when associated with a-24; a-26; d-76 and a
76	monomeric form. does not dimerize. weakly interacts with c1q domain of cbln1. forms intermediate synapse. abolishes cere
342	reduces binding to cbln1; when associated with d76.
343	no effect on cbln1 interaction; when associated with d76. no effect on cbln1 binding; when associated with d-76; a-346;
344	no effect on cbln1 interaction; when associated with d76.
345	reduces binding to cbln1; when associated with d76. abolishes cbln1 binding; when associated with a-24; a-26; a-61 and d
346	no effect on cbln1 interaction; when associated with d76. no effect on cbln1 binding; when associated with d-76; a-343;
348	reduces binding to cbln1; when associated with d76.
349	no effect on cbln1 interaction; when associated with d76. no effect on cbln1 binding; when associated with d-76; a-343;
350	no effect on cbln1 interaction; when associated with d76. no effect on cbln1 binding; when associated with d-76; a-343;
352	reduces binding to cbln1; when associated with d76.
364	no effect on cbln1 interaction; when associated with d76.
434	impairs the ability of the lbd to induce pore closure. no effect on synapse assembly. no effect on cerebellar parallel f
617	abolishes activation by gria1 of cation-channel activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 439 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, RRAGTTGT_UNKNOWN, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, GOMF_GLUTAMATE_GATED_RECEPTOR_ACTIVITY, GAANYNYGACNY_UNKNOWN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SYNAPSE_ASSEMBLY, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_CEREBELLAR_CORTEX_MORPHOGENESIS

GO Biological Process (23): heterophilic cell-cell adhesion (GO:0007157), glutamate receptor signaling pathway (GO:0007215), intracellular protein localization (GO:0008104), regulation of neuron projection development (GO:0010975), cerebellar granule cell differentiation (GO:0021707), synaptic transmission, glutamatergic (GO:0035249), regulation of neuron apoptotic process (GO:0043523), modulation of chemical synaptic transmission (GO:0050804), positive regulation of synapse assembly (GO:0051965), excitatory postsynaptic potential (GO:0060079), prepulse inhibition (GO:0060134), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072), regulation of postsynaptic density assembly (GO:0099151), synaptic signaling via neuropeptide (GO:0099538), positive regulation of long-term synaptic depression (GO:1900454), excitatory synapse assembly (GO:1904861), regulation of presynapse assembly (GO:1905606), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), ionotropic glutamate receptor signaling pathway (GO:0035235), regulation of synaptic plasticity (GO:0048167), regulation of synapse assembly (GO:0051963), regulation of postsynaptic membrane potential (GO:0060078)

GO Molecular Function (11): AMPA glutamate receptor activity (GO:0004971), glutamate receptor activity (GO:0008066), PDZ domain binding (GO:0030165), identical protein binding (GO:0042802), metal ion binding (GO:0046872), scaffold protein binding (GO:0097110), transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential (GO:1904315), monoatomic ion channel activity (GO:0005216), protein binding (GO:0005515), ligand-gated monoatomic ion channel activity (GO:0015276), signaling receptor activity (GO:0038023)

GO Cellular Component (12): plasma membrane (GO:0005886), ionotropic glutamate receptor complex (GO:0008328), AMPA glutamate receptor complex (GO:0032281), dendritic spine (GO:0043197), synapse (GO:0045202), parallel fiber to Purkinje cell synapse (GO:0098688), trans-synaptic protein complex (GO:0098820), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020), somatodendritic compartment (GO:0036477), postsynaptic membrane (GO:0045211)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chemical synaptic transmission	2
synapse assembly	2
regulation of synapse assembly	2
regulation of postsynaptic membrane potential	2
glutamate-gated receptor activity	2
protein binding	2
postsynapse	2
cellular anatomical structure	2
cell-cell adhesion	1
cell surface receptor signaling pathway	1
glutamate receptor activity	1
macromolecule localization	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
cell differentiation in hindbrain	1
cerebellar granular layer formation	1
central nervous system neuron differentiation	1
glutamatergic neuron differentiation	1
regulation of apoptotic process	1
neuron apoptotic process	1
regulation of trans-synaptic signaling	1
positive regulation of nervous system development	1
positive regulation of cell junction assembly	1
chemical synaptic transmission, postsynaptic	1
startle response	1
negative regulation of response to external stimulus	1
regulation of biological quality	1
postsynaptic density assembly	1
regulation of postsynaptic specialization assembly	1
regulation of excitatory synapse assembly	1
regulation of postsynaptic density organization	1
synaptic signaling	1
positive regulation of biological process	1
long-term synaptic depression	1
regulation of long-term synaptic depression	1
presynapse assembly	1
regulation of presynapse organization	1
transport	1
monoatomic ion transport	1
transmembrane transport	1

Protein interactions and networks

STRING

1876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRID2	CBLN1	P02682	994
GRID2	GRID2IP	A4D2P6	978
GRID2	NRXN1	Q9ULB1	893
GRID2	NRXN2	Q9P2S2	861
GRID2	CBLN3	Q6UW01	861
GRID2	BECN1	Q14457	789
GRID2	CBLN2	Q8IUK8	730
GRID2	SPTBN2	O15020	726
GRID2	SLC1A6	P48664	700
GRID2	GOPC	Q9HD26	664
GRID2	SHANK2	Q9UPX8	632
GRID2	PTPN4	P29074	616
GRID2	GRM1	Q13255	608
GRID2	DLG2	Q15700	607
GRID2	CBLN4	Q9NTU7	606

IntAct

126 interactions, top by confidence:

A	B	Type	Score
Magi2	GRID2	psi-mi:“MI:0915”(physical association)	0.510
GRID2	Magi2	psi-mi:“MI:0915”(physical association)	0.510
PDZD2	GRID2	psi-mi:“MI:0407”(direct interaction)	0.440
SYNJ2BP	GRID2	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
WHRN	GRID2	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
MAST1	GRID2	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	APBA3	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	GRIP2	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	TJP1	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
GRID2	CARD11	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (17): GRID2IP (Two-hybrid), GRID2 (Affinity Capture-Western), GRIA1 (Affinity Capture-Western), GRID2 (Affinity Capture-Western), GRIK2 (Affinity Capture-Western), GRID2 (Affinity Capture-Western), GRID2 (Affinity Capture-Western), GRID2 (Affinity Capture-Western), GOPC (Two-hybrid), PTPN4 (Two-hybrid), GRID2 (Affinity Capture-Western), GRID2IP (Reconstituted Complex), GRID2IP (Affinity Capture-Western), GRID2 (Affinity Capture-MS), GRID2 (Affinity Capture-MS)

ESM2 similar proteins: A0A078BQP2, A0A1J0M738, A8WPG9, B1Q257, E7EAU8, E9NA96, G5EFQ0, H2L002, N1NVB7, O43424, O62026, O62179, P23897, P25092, P26591, P34299, P55204, Q01812, Q03445, Q07553, Q09435, Q10015, Q10028, Q10029, Q10914, Q16099, Q19187, Q20086, Q21415, Q23310, Q23681, Q23682, Q3UWA6, Q5IS46, Q60934, Q61625, Q61627, Q62640, Q63226, Q68Y21

Diamond homologs: A0A2R8QF68, A7XY94, B1AS29, B7ZSK1, O15399, O43424, O60391, P0AEQ3, P0AEQ4, P0AEQ5, P22756, P35436, P39086, P42264, Q00959, Q00960, Q00961, Q01097, Q01098, Q01812, Q03391, Q10914, Q12879, Q13003, Q13224, Q14957, Q38PU2, Q38PU4, Q5IS45, Q5R1P3, Q60934, Q61625, Q62645, Q63226, Q68Y21, P19439, Q16099, Q16478, Q21415, Q5IS46

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
“glutamic acid”	“up-regulates activity”	GRID2	“chemical activation”
GRID2IP	“up-regulates quantity”	GRID2	binding
GRID2	“up-regulates quantity”	calcium(2+)	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	53.9×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	51.3×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	51.3×	1e-06
Long-term potentiation	5	44.9×	2e-06
Assembly and cell surface presentation of NMDA receptors	9	43.1×	8e-11
Neurexins and neuroligins	9	33.4×	5e-10
Protein-protein interactions at synapses	5	25.1×	4e-05
RHOB GTPase cycle	5	14.6×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	82.0×	2e-16
receptor clustering	7	56.0×	7e-09
protein localization to synapse	5	49.1×	3e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	7	44.5×	3e-08
cell-cell adhesion	10	13.0×	4e-07
protein-containing complex assembly	7	10.2×	2e-04
regulation of small GTPase mediated signal transduction	5	9.2×	4e-03
chemical synaptic transmission	7	6.9×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

364 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	9
Uncertain significance	183
Likely benign	88
Benign	41

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1723284	NC_000004.11:g.(93511438_94006145)_(94032105_94128554)del	Pathogenic
180131	NC_000004.12:g.93013415_93157863del	Pathogenic
180132	NM_001510.3(GRID2):c.530-12057_735+24661del36924	Pathogenic
180133	NC_000004.12:g.92559959_92610106del	Pathogenic
180134	NC_000004.12:g.92491792_92826931del	Pathogenic
2424191	NC_000004.11:g.(?93511262)(93511457_?)del	Pathogenic
2424192	NC_000004.11:g.(?94006126)(94032124_?)del	Pathogenic
242880	Single allele	Pathogenic
2579188	GRCh38/hg38 4q22.1(chr4:92303869-92304842)x0	Pathogenic
427806	NM_001510.4(GRID2):c.2128C>T (p.Arg710Trp)	Pathogenic
442959	GRCh37/hg19 4q22.2(chr4:93978239-94073948)x0	Pathogenic
685734	GRCh37/hg19 4q22.1-22.2(chr4:93426934-93754475)x1	Pathogenic
688260	GRCh37/hg19 4q22.1(chr4:93326311-93569881)x1	Pathogenic
930201	NM_001510.4(GRID2):c.568C>T (p.Gln190Ter)	Pathogenic
985445	NM_001510.4(GRID2):c.1961C>G (p.Ala654Gly)	Pathogenic
155066	GRCh38/hg38 4q22.2(chr4:92833132-93124343)x1	Likely pathogenic
1696205	NC_000004.11:g.(93511438_94006145)_(94006431_94031898)del	Likely pathogenic
1723717	NM_001510.4(GRID2):c.1949C>T (p.Ala650Val)	Likely pathogenic
488523	NM_001510.4(GRID2):c.671G>A (p.Arg224Gln)	Likely pathogenic
545306	NC_000004.12:g.(?92590068)(92732357_?)del	Likely pathogenic
545307	NC_000004.12:g.(?92930845)(93092974_?)del	Likely pathogenic
620343	NM_001510.4(GRID2):c.53G>A (p.Trp18Ter)	Likely pathogenic
800978	NM_001510.4(GRID2):c.910C>T (p.Arg304Ter)	Likely pathogenic
992352	NM_001510.4(GRID2):c.1913G>A (p.Trp638Ter)	Likely pathogenic

SpliceAI

3903 predictions. Top by Δscore:

Variant	Effect	Δscore
4:92590126:TCTA:T	acceptor_loss	1.0000
4:92590127:CTA:C	acceptor_loss	1.0000
4:92590128:TA:T	acceptor_loss	1.0000
4:92590129:A:AG	acceptor_gain	1.0000
4:92590129:AG:A	acceptor_gain	1.0000
4:92590130:G:GA	acceptor_gain	1.0000
4:92590130:GG:G	acceptor_gain	1.0000
4:92590130:GGA:G	acceptor_gain	1.0000
4:92590130:GGAGC:G	acceptor_gain	1.0000
4:92590282:AGAAG:A	donor_gain	1.0000
4:92590283:GAAG:G	donor_gain	1.0000
4:92590283:GAAGG:G	donor_gain	1.0000
4:92590287:G:C	donor_loss	1.0000
4:92590287:G:GG	donor_gain	1.0000
4:92590288:T:G	donor_loss	1.0000
4:92437756:T:G	acceptor_gain	0.9900
4:92515061:G:GT	donor_gain	0.9900
4:92515061:G:T	donor_gain	0.9900
4:92590120:C:G	acceptor_gain	0.9900
4:92590127:CTAGG:C	acceptor_gain	0.9900
4:92590128:TAGG:T	acceptor_gain	0.9900
4:92590129:AGGA:A	acceptor_gain	0.9900
4:92590130:GGAG:G	acceptor_gain	0.9900
4:92590285:AG:A	donor_gain	0.9900
4:92590286:GG:G	donor_gain	0.9900
4:92738747:GCT:G	donor_gain	0.9900
4:92831218:T:G	acceptor_gain	0.9900
4:92372655:T:TA	acceptor_gain	0.9800
4:92687285:A:G	donor_gain	0.9800
4:92728249:A:AG	acceptor_gain	0.9800

AlphaMissense

6625 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:92304744:G:A	G30R	1.000
4:92304744:G:C	G30R	1.000
4:92590131:G:A	G30E	1.000
4:92590173:T:C	F44S	1.000
4:92590181:G:C	A47P	1.000
4:92590269:T:G	F76C	1.000
4:92590286:G:C	A82P	1.000
4:93084997:T:A	C83S	1.000
4:93084997:T:C	C83R	1.000
4:93084998:G:A	C83Y	1.000
4:93084998:G:C	C83S	1.000
4:93084998:G:T	C83F	1.000
4:93084999:T:G	C83W	1.000
4:93085004:T:C	L85P	1.000
4:93085015:G:T	G89C	1.000
4:93085016:G:T	G89V	1.000
4:93085025:C:A	A92D	1.000
4:93085028:T:C	L93P	1.000
4:93085033:A:C	S95R	1.000
4:93085035:C:A	S95R	1.000
4:93085035:C:G	S95R	1.000
4:93085064:T:C	L105P	1.000
4:93085094:C:A	P115H	1.000
4:93085094:C:G	P115R	1.000
4:93085100:T:C	L117P	1.000
4:93085243:T:A	W165R	1.000
4:93085243:T:C	W165R	1.000
4:93207440:T:A	W258R	1.000
4:93207440:T:C	W258R	1.000
4:93216802:G:C	R285P	1.000

dbSNP variants (sampled 300 via entrez): RS1000000909 (4:93648404 G>A), RS1000005524 (4:93132111 A>T), RS1000006528 (4:93300924 T>G), RS1000006814 (4:92617228 T>A), RS1000007656 (4:93710263 G>A,T), RS1000008392 (4:92700854 A>T), RS1000008687 (4:93773778 C>A), RS1000009002 (4:92737646 G>T), RS1000009771 (4:93665658 A>C), RS1000011273 (4:92605063 C>A), RS1000014060 (4:93052948 T>C,G), RS1000017933 (4:92335911 A>G), RS1000019692 (4:93508710 G>A), RS1000020572 (4:93276608 T>G), RS1000021978 (4:93567613 T>C)

Disease associations

OMIM: gene MIM:602368 | disease phenotypes: MIM:616204, MIM:275900, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive spinocerebellar ataxia 18	Strong	Autosomal recessive

Mondo (3): autosomal recessive spinocerebellar ataxia 18 (MONDO:0014530), Troyer syndrome (MONDO:0010156), schizophrenia (MONDO:0005090)

Orphanet (3): Autosomal recessive congenital cerebellar ataxia due to GRID2 deficiency (Orphanet:363432), Autosomal recessive spastic paraplegia type 20 (Orphanet:101000), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000543	Optic disc pallor
HP:0000565	Esotropia
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000657	Oculomotor apraxia
HP:0000666	Horizontal nystagmus
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001310	Dysmetria
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002075	Dysdiadochokinesis
HP:0002078	Truncal ataxia
HP:0002167	Abnormal speech pattern
HP:0002311	Incoordination
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0004302	Functional motor deficit
HP:0006855	Cerebellar vermis atrophy
HP:0012444	Brain atrophy

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001762_184	Obesity-related traits	8.000000e-06
GCST002932_32	Manganese levels	3.000000e-06
GCST003264_179	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST003264_243	Post bronchodilator FEV1/FVC ratio	4.000000e-06
GCST003264_462	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST003264_933	Post bronchodilator FEV1/FVC ratio	5.000000e-06
GCST005316_598	Intelligence (MTAG)	4.000000e-08
GCST007208_5	Obsessive-compulsive disorder	3.000000e-06
GCST007208_8	Obsessive-compulsive disorder	6.000000e-06
GCST008526_64	Coffee consumption	3.000000e-06
GCST009391_870	Metabolite levels	3.000000e-06
GCST011569_2	Pancreatic beta-cell glucose sensitivity	4.000000e-07
GCST011703_66	Smoking initiation	2.000000e-08
GCST012194_11	Obsessive-compulsive traits	2.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement
EFO:0004713	FEV/FVC ratio
EFO:0004337	intelligence
EFO:0006781	coffee consumption measurement
EFO:0010535	sucrose measurement
EFO:0006842	diabetes mellitus biomarker
EFO:0005670	smoking initiation

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536858	Spastic paraplegia 20, autosomal recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4524129 (PROTEIN COMPLEX GROUP)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1875705	Efficacy	3	risperidone

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1875705	GRID2	3	0.00	1	risperidone
rs558364281	GRID2		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: lgic — Ionotropic glutamate receptors

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects methylation, decreases expression	2
FR900359	decreases phosphorylation	1
methyleugenol	decreases expression	1
sodium arsenite	increases expression	1
casticin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Amphotericin B	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Lead	affects expression	1
Menthol	increases expression	1
Dronabinol	increases expression	1
Triclosan	decreases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4886917	Binding	Glutamate, Non-Selective Eurofins-Panlabs radioligand binding assay	Profiling data from Eurofins-Panlabs

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety