GRIK3

Summary

GRIK3 (glutamate ionotropic receptor kainate type subunit 3, HGNC:4581) is a protein-coding gene on chromosome 1p34.3, encoding Glutamate receptor ionotropic, kainate 3 (Q13003). Ionotropic glutamate receptor that functions as a cation-permeable ligand-gated ion channel, gated by L-glutamate and the glutamatergic agonist kainic acid.

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to the kainate family of glutamate receptors, which are composed of four subunits and function as ligand-activated ion channels. It is not certain if the subunit encoded by this gene is subject to RNA editing as the other 2 family members (GRIK1 and GRIK2). A Ser310Ala polymorphism has been associated with schizophrenia, and there are conflicting reports of its association with the pathogenesis of delirium tremens in alcoholics.

Source: NCBI Gene 2899 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 129 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000831

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4581
Approved symbol	GRIK3
Name	glutamate ionotropic receptor kainate type subunit 3
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	GluK3, GLUR7
Ensembl gene	ENSG00000163873
Ensembl biotype	protein_coding
OMIM	138243
Entrez	2899

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000373091, ENST00000373093, ENST00000462621, ENST00000479620

RefSeq mRNA: 1 — MANE Select: NM_000831 NM_000831

CCDS: CCDS416

Canonical transcript exons

ENST00000373091 — 16 exons

Exon	Start	End
ENSE00001079193	36869748	36869801
ENSE00001079195	36841736	36841939
ENSE00001079196	36872188	36872369
ENSE00001079197	36880634	36880891
ENSE00001079198	36859844	36860017
ENSE00001079202	36859108	36859251
ENSE00001200395	36804987	36805237
ENSE00001200400	36806104	36806326
ENSE00001200452	36890920	36891096
ENSE00001459494	36795527	36802045
ENSE00001671819	36825603	36825826
ENSE00001696975	36817060	36817277
ENSE00001704349	36819736	36819854
ENSE00001836405	37033994	37034515
ENSE00003521730	36850311	36850424
ENSE00003527069	36853615	36853722

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 96.35.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0102 / max 165.2992, expressed in 289 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11760	0.7520	192
11757	0.6359	164
11759	0.5335	167
201470	0.0511	32
11758	0.0375	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	96.35	gold quality
sural nerve	UBERON:0015488	91.66	gold quality
tibial nerve	UBERON:0001323	82.29	gold quality
dorsal root ganglion	UBERON:0000044	79.52	gold quality
trigeminal ganglion	UBERON:0001675	76.37	gold quality
prefrontal cortex	UBERON:0000451	76.20	gold quality
endothelial cell	CL:0000115	75.50	silver quality
primary visual cortex	UBERON:0002436	75.50	gold quality
hypothalamus	UBERON:0001898	75.15	gold quality
neocortex	UBERON:0001950	74.78	gold quality
anterior cingulate cortex	UBERON:0009835	74.71	gold quality
right frontal lobe	UBERON:0002810	74.61	gold quality
frontal cortex	UBERON:0001870	74.35	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.27	gold quality
muscle layer of sigmoid colon	UBERON:0035805	74.24	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	73.93	gold quality
cerebral cortex	UBERON:0000956	72.98	gold quality
Brodmann (1909) area 23	UBERON:0013554	72.71	gold quality
substantia nigra	UBERON:0002038	72.68	gold quality
medial globus pallidus	UBERON:0002477	71.96	gold quality
lower esophagus muscularis layer	UBERON:0035833	71.79	gold quality
lower esophagus	UBERON:0013473	71.74	gold quality
Brodmann (1909) area 46	UBERON:0006483	71.41	gold quality
occipital lobe	UBERON:0002021	71.25	gold quality
midbrain	UBERON:0001891	70.90	gold quality
right hemisphere of cerebellum	UBERON:0014890	70.38	gold quality
superior frontal gyrus	UBERON:0002661	70.30	gold quality
ganglionic eminence	UBERON:0004023	70.01	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	69.82	gold quality
forebrain	UBERON:0001890	69.78	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	469.67
E-ANND-3	yes	5.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

312 targeting GRIK3, 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-8485	100.00	77.57	4731
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996

Literature-anchored findings (GeneRIF, showing 16)

• Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia. (PMID:11986986)
• Using three single nucleotide polymorphisms in GRIK2 and one in GRIK3, we found no evidence for association with Obssessive-Compulsive disorder in case-control or family-based analyses. (PMID:15094479)
• suggestive for a significant role of GRIK3 polymorphism in the pathogenesis of delirium tremens in alcohol-dependent individuals (PMID:16314883)
• These findings do not seem to support the hypothesis of the role of this polymorphism in the pathogenesis of alcoholism. (PMID:16356644)
• significant linkage disequilibrium (LD) indicated by preferential maternal transmission of the GluR7 S310 allele to recurrent major depressive disorder patients (P = 0.012), but not to bipolar I disorder (BPI) patients (P = 1.00) (PMID:16958029)
• The present results, although not robust, support the importance of more extensive investigations of GRIK3, given its potential role in mediating risk for schizophrenia. (PMID:19022628)
• functional GRIK3 Ser310Ala polymorphism is homozygosity is associated with higher scores in harm avoidance and respective subscales of personality traits (PMID:19221446)
• Our study suggests a potential role for GRIK3 for susceptibility to schizophrenia in Indian population. (PMID:19921975)
• Some support (at a nominal significance level of 0.05/0.01) was found for association between GRIK3 and depression. (PMID:20052609)
• Our results suggest that the analysed polymorphisms ofANKK1 and ADH4 can play an important part in the pathogenesis of alcohol abuse (PMID:22232963)
• Analyses revealed that polymorphism Ser310Ala of GRIK3 gene is not associated with alcohol dependence or any of its subgroups. (PMID:23006490)
• 1p34.3 deletion involving GRIK3: Further clinical implication of GRIK family glutamate receptors in the pathogenesis of developmental delay. (PMID:24449200)
• GRIK3 expression is significantly downregulated in human masticatory mucosa during wound healing (PMID:28005267)
• additional experiment showed that the lymph node metastasis tissues had higher GRIK3 expression than their matched primary gastric cancer (GC) tissues. These findings suggested that elevated GRIK3 expression could serve as an independent prognostic biomarker and a novel potential treatment target for patients with GC. (PMID:28631555)
• Mechanically, GRIK3 influenced a range of signaling pathways and key signal transducers, including two epithelial-mesenchymal transition regulators, SPDEF and CDH1. Moreover, overexpression of GRIK3 increased the expression of mesenchymal markers and decreased the expression of epithelial markers, resulting in the translocation of beta-catenin into the nucleus and the increased beta-catenin transcriptional activity. (PMID:30977227)
• CircASXL1 knockdown represses the progression of colorectal cancer by downregulating GRIK3 expression by sponging miR-1205. (PMID:34127015)

Cross-species orthologs

42 orthologs

Organism	Symbol	Gene ID
danio_rerio	grik3	ENSDARG00000077715
mus_musculus	Grik3	ENSMUSG00000001985
rattus_norvegicus	Grik3	ENSRNOG00000008992
drosophila_melanogaster	GluRIA	FBGN0004619
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	Ir68b	FBGN0036250
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	Ekar	FBGN0039916
drosophila_melanogaster	CG11155	FBGN0039927
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
drosophila_melanogaster	GluRIB	FBGN0264000
caenorhabditis_elegans		WBGENE00001612
caenorhabditis_elegans	glr-3	WBGENE00001614
caenorhabditis_elegans		WBGENE00001618
caenorhabditis_elegans		WBGENE00003775
caenorhabditis_elegans		WBGENE00012190

Paralogs (17): GRIN2D (ENSG00000105464), GRIK5 (ENSG00000105737), GRIN3B (ENSG00000116032), GRIA2 (ENSG00000120251), GRIA3 (ENSG00000125675), GRIK4 (ENSG00000149403), GRID2 (ENSG00000152208), GRIA4 (ENSG00000152578), GRIA1 (ENSG00000155511), GRIN2C (ENSG00000161509), GRIK2 (ENSG00000164418), GRIK1 (ENSG00000171189), GRIN1 (ENSG00000176884), GRID1 (ENSG00000182771), GRIN2A (ENSG00000183454), GRIN3A (ENSG00000198785), GRIN2B (ENSG00000273079)

Protein

Protein identifiers

Glutamate receptor ionotropic, kainate 3 — Q13003 (reviewed: Q13003)

Alternative names: Excitatory amino acid receptor 5, Glutamate receptor 7

All UniProt accessions (1): Q13003

UniProt curated annotations — full annotation on UniProt →

Function. Ionotropic glutamate receptor that functions as a cation-permeable ligand-gated ion channel, gated by L-glutamate and the glutamatergic agonist kainic acid. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In association with GRIK2, involved in presynaptic facilitation of glutamate release at hippocampal mossy fiber synapses.

Subunit / interactions. Homotetramer, and heterotetramer with either GRIK4 or GRIK5. Can form functional heteromeric receptors with GRIK2. Interacts with PRKCABP. Interacts with NETO2.

Subcellular location. Cell membrane. Postsynaptic cell membrane.

Miscellaneous. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds domoate > kainate » L-glutamate = quisqualate » AMPA = NMDA.

Similarity. Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIK3 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13003-1	1	yes
Q13003-2	2

RefSeq proteins (1): NP_000822* (*=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), 1 shown:

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

UniProt features (36 total): glycosylation site 10, binding site 6, topological domain 4, sequence variant 4, transmembrane region 3, sequence conflict 3, signal peptide 1, chain 1, modified residue 1, disulfide bond 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13003-F1	82.48	0.45

Functional residue map

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

Ligand- & substrate-binding residues (6): 520; 525; 691; 692; 739; 518

Post-translational modifications (2): 869, 887

Disulfide bonds (1): 99–350

Glycosylation sites (10): 70, 76, 278, 381, 415, 426, 433, 548, 551, 752

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-451308	Activation of Ca-permeable Kainate Receptor
R-HSA-500657	Presynaptic function of Kainate receptors

MSigDB gene sets: 266 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, FXR_IR1_Q6, REACTOME_IONOTROPIC_ACTIVITY_OF_KAINATE_RECEPTORS, BROWNE_HCMV_INFECTION_6HR_DN, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, GOMF_GLUTAMATE_GATED_RECEPTOR_ACTIVITY, RORA1_01, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GCANCTGNY_MYOD_Q6, GOZGIT_ESR1_TARGETS_DN, MAZ_Q6, AP4_Q6, TGACCTY_ERR1_Q2, GOBP_G_PROTEIN_COUPLED_GLUTAMATE_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (13): glutamate receptor signaling pathway (GO:0007215), G protein-coupled glutamate receptor signaling pathway (GO:0007216), synaptic transmission, glutamatergic (GO:0035249), regulation of membrane potential (GO:0042391), modulation of chemical synaptic transmission (GO:0050804), negative regulation of synaptic transmission, glutamatergic (GO:0051967), monoatomic ion transport (GO:0006811), adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway (GO:0007196), calcium-mediated signaling (GO:0019722), monoatomic ion transmembrane transport (GO:0034220), ionotropic glutamate receptor signaling pathway (GO:0035235), regulation of postsynaptic membrane potential (GO:0060078), regulation of presynaptic membrane potential (GO:0099505)

GO Molecular Function (10): adenylate cyclase inhibiting G protein-coupled glutamate receptor activity (GO:0001640), glutamate-gated receptor activity (GO:0004970), glutamate receptor activity (GO:0008066), kainate selective glutamate receptor activity (GO:0015277), glutamate-gated calcium ion channel activity (GO:0022849), ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential (GO:0099507), transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential (GO:1904315), monoatomic ion channel activity (GO:0005216), ligand-gated monoatomic ion channel activity (GO:0015276), signaling receptor activity (GO:0038023)

GO Cellular Component (13): plasma membrane (GO:0005886), axon (GO:0030424), dendrite (GO:0030425), dendrite cytoplasm (GO:0032839), kainate selective glutamate receptor complex (GO:0032983), presynaptic membrane (GO:0042734), terminal bouton (GO:0043195), perikaryon (GO:0043204), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ionotropic activity of kainate receptors	1
Activation of kainate receptors upon glutamate binding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glutamate-gated receptor activity	3
glutamate receptor activity	2
glutamate receptor signaling pathway	2
G protein-coupled glutamate receptor activity	2
chemical synaptic transmission	2
regulation of membrane potential	2
transmitter-gated monoatomic ion channel activity	2
neuron projection	2
synaptic membrane	2
presynapse	2
cellular anatomical structure	2
cell surface receptor signaling pathway	1
G protein-coupled receptor signaling pathway	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
regulation of trans-synaptic signaling	1
synaptic transmission, glutamatergic	1
negative regulation of synaptic transmission	1
regulation of synaptic transmission, glutamatergic	1
transport	1
adenylate cyclase inhibiting G protein-coupled glutamate receptor activity	1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1
G protein-coupled glutamate receptor signaling pathway	1
intracellular signaling cassette	1
monoatomic ion transport	1
transmembrane transport	1
ligand-gated ion channel signaling pathway	1
adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway	1
dicarboxylic acid transmembrane transporter activity	1
amino acid transmembrane transporter activity	1
ionotropic glutamate receptor signaling pathway	1
transmembrane signaling receptor activity	1
glutamate binding	1
potassium channel activity	1
ligand-gated sodium channel activity	1
ligand-gated calcium channel activity	1
ligand-gated monoatomic ion channel activity	1
presynaptic membrane	1
regulation of presynaptic membrane potential	1
regulation of postsynaptic membrane potential	1

Protein interactions and networks

STRING

1792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRIK3	GRIK4	Q16099	978
GRIK3	GRIK1	P39086	977
GRIK3	GRIK2	Q13002	967
GRIK3	GRIK5	Q16478	955
GRIK3	KARS1	Q15046	660
GRIK3	GRM2	Q14416	616
GRIK3	ARB2A	Q8WUF8	601
GRIK3	SENP1	Q9P0U3	580
GRIK3	GRM6	O15303	568
GRIK3	GRIA1	P42261	563
GRIK3	PLAC8L1	A1L4L8	561
GRIK3	GRM4	Q14833	527
GRIK3	GRM3	Q14832	524
GRIK3	CHRNB2	P17787	524
GRIK3	NETO1	Q8TDF5	507

IntAct

2 interactions, top by confidence:

A	B	Type	Score
GRIK3	SSR3	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (11): GRIK3 (Synthetic Lethality), SSR3 (Proximity Label-MS), GRIK5 (Affinity Capture-Western), GRIK3 (Reconstituted Complex), GRIK3 (Co-fractionation), GRIK1 (Reconstituted Complex), GRIK4 (Reconstituted Complex), GRIK3 (Co-crystal Structure), GRIK3 (Co-fractionation), GRIK3 (Co-fractionation), GRIK3 (Co-fractionation)

ESM2 similar proteins: A0A2R8QF68, B1AS29, P19439, P19490, P19491, P19492, P19493, P20262, P22756, P23818, P23819, P26591, P31422, P34299, P39086, P39087, P42260, P42261, P42262, P42263, P42264, P48058, Q01812, Q03445, Q13002, Q13003, Q14832, Q16099, Q16478, Q1ZZH1, Q21415, Q38PU2, Q38PU3, Q38PU4, Q38PU5, Q38PU6, Q38PU7, Q38PU8, Q5IS46, Q5R4M0

Diamond homologs: A0A2R8QF68, A7XY94, B1AS29, E9NA96, P19439, P19490, P19491, P19492, P19493, P20262, P22756, P23818, P23819, P26591, P34299, P35436, P39086, P39087, P42260, P42261, P42262, P42263, P42264, P48058, Q00959, Q01812, Q03445, Q10914, Q12879, Q13002, Q13003, Q16099, Q16478, Q21415, Q38PU2, Q38PU3, Q38PU4, Q38PU5, Q38PU6, Q38PU7

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
GRIK3	up-regulates	Excitatory_synaptic_transmission
“glutamic acid”	“up-regulates activity”	GRIK3	“chemical activation”
GRIK3	“up-regulates quantity”	calcium(2+)	relocalization
GRIK3	“up-regulates quantity”	D-serine	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	104
Likely benign	7
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

4095 predictions. Top by Δscore:

Variant	Effect	Δscore
1:36801894:T:A	donor_gain	1.0000
1:36804981:GCTTA:G	donor_loss	1.0000
1:36804982:CTTA:C	donor_loss	1.0000
1:36804983:TTA:T	donor_loss	1.0000
1:36804984:TA:T	donor_loss	1.0000
1:36804985:ACC:A	donor_loss	1.0000
1:36804986:CCTG:C	donor_gain	1.0000
1:36805238:C:A	acceptor_loss	1.0000
1:36805238:C:CC	acceptor_gain	1.0000
1:36805239:T:A	acceptor_loss	1.0000
1:36806099:CTCA:C	donor_loss	1.0000
1:36806101:CAC:C	donor_loss	1.0000
1:36806102:A:AC	donor_gain	1.0000
1:36806102:AC:A	donor_gain	1.0000
1:36806102:ACC:A	donor_gain	1.0000
1:36806102:ACCC:A	donor_loss	1.0000
1:36806103:C:CC	donor_gain	1.0000
1:36806103:C:CT	donor_loss	1.0000
1:36806103:CC:C	donor_gain	1.0000
1:36806103:CCC:C	donor_gain	1.0000
1:36806125:AGC:A	donor_gain	1.0000
1:36806332:CCG:C	acceptor_gain	1.0000
1:36806333:C:CT	acceptor_gain	1.0000
1:36806333:C:T	acceptor_gain	1.0000
1:36806334:G:C	acceptor_gain	1.0000
1:36806334:G:GC	acceptor_gain	1.0000
1:36806334:G:T	acceptor_gain	1.0000
1:36817054:CCTCA:C	donor_loss	1.0000
1:36817055:CTCAC:C	donor_loss	1.0000
1:36817056:TCAC:T	donor_loss	1.0000

AlphaMissense

6066 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:36825626:G:C	S577R	1.000
1:36825626:G:T	S577R	1.000
1:36825628:T:G	S577R	1.000
1:36859136:C:T	G359D	1.000
1:36859146:A:G	W356R	1.000
1:36859146:A:T	W356R	1.000
1:36859163:C:G	C350S	1.000
1:36859164:A:G	C350R	1.000
1:36859164:A:T	C350S	1.000
1:36859227:C:G	A329P	1.000
1:36859229:T:A	D328V	1.000
1:36859230:C:G	D328H	1.000
1:36872267:A:G	L218P	1.000
1:36872306:C:G	R205P	1.000
1:36872348:A:G	L191P	1.000
1:36872357:A:G	L188P	1.000
1:36872366:A:G	L185P	1.000
1:36872366:A:T	L185H	1.000
1:36880651:A:T	V178D	1.000
1:36880670:A:G	W172R	1.000
1:36880670:A:T	W172R	1.000
1:36880792:G:C	P131R	1.000
1:36880792:G:T	P131H	1.000
1:36880801:A:G	L128P	1.000
1:36880809:G:C	C125W	1.000
1:36880810:C:T	C125Y	1.000
1:36880822:A:T	V121D	1.000
1:36880853:C:G	G111R	1.000
1:36880879:A:G	L102P	1.000
1:36880887:A:C	C99W	1.000

dbSNP variants (sampled 300 via entrez): RS1000019987 (1:36969434 A>T), RS1000022807 (1:37034709 G>A,T), RS1000047506 (1:36818956 C>G,T), RS1000059238 (1:36880706 T>A), RS1000060704 (1:37008522 C>A), RS1000067915 (1:37004603 T>C), RS1000075088 (1:36944825 C>T), RS1000086897 (1:37014325 A>G), RS1000096035 (1:36998175 C>T), RS1000096311 (1:36871276 A>G), RS1000120068 (1:37004888 C>T), RS1000138011 (1:36804165 G>A,T), RS1000148443 (1:36989467 G>A), RS1000151979 (1:36828893 G>A), RS1000165607 (1:36824312 T>C)

Disease associations

OMIM: gene MIM:138243 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001851_1	Schizophrenia	3.000000e-07
GCST003264_173	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_465	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST003264_495	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST003447_1	Neuroticism	4.000000e-08
GCST004571_24	Iron status biomarkers (total iron binding capacity)	9.000000e-07
GCST004572_5	Iron status biomarkers (transferrin saturation)	9.000000e-07
GCST004800_2	Forced expiratory volume in 1 second (environmental tobacco smoke interaction)	7.000000e-06
GCST008466_11	Alanine aminotransferase levels in non-alcoholic fatty liver disease	6.000000e-06
GCST009391_548	Metabolite levels	7.000000e-06
GCST009600_16	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	1.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0007660	neuroticism measurement
EFO:0006334	total iron binding capacity
EFO:0004314	forced expiratory volume
EFO:0008361	environmental tobacco smoke exposure measurement
EFO:0010496	hippuric acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2109241 (PROTEIN COMPLEX GROUP), CHEMBL3684 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 944,840 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL575060	GLUTAMIC ACID	3	929,756
CHEMBL275040	KAINIC ACID	2	15,084

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1334802	Toxicity	3	antipsychotics	Psychotic Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1334802	GRIK3	3	3.00	1	antipsychotics
rs6691840	GRIK3		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — Ionotropic glutamate receptors

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
domoic acid	Agonist	8.42	pKi
SYM2081	Full agonist	8.24	pKi
kainate	Full agonist	7.48	pKi
[3H]UBP310	Antagonist	6.3	pKd

Binding affinities (BindingDB)

1 measured of 3 human assays (3 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
LY-293558	KI	3200 nM

ChEMBL bioactivities

56 potent at pChembl≥5 of 72 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.31	Ki	4.84	nM	DOMOIC ACID
8.00	Ki	10	nM	KAINIC ACID
7.38	Ki	42	nM	CHEMBL59284
7.34	Ki	46	nM	CHEMBL13076
7.16	Ki	70	nM	CHEMBL13076
7.11	IC50	77	nM	KAINIC ACID
6.96	Ki	110	nM	CHEMBL12696
6.96	Ki	110	nM	CHEMBL273675
6.85	Ki	142	nM	CHEMBL5193862
6.39	Ki	410	nM	CHEMBL268284
6.37	Ki	423	nM	CHEMBL58590
6.29	Ki	518	nM	CHEMBL299180
6.28	Ki	530	nM	CHEMBL416685
6.21	Ki	617	nM	CHEMBL301536
6.17	Ki	680	nM	CHEMBL63861
6.16	Ki	700	nM	CHEMBL84142
6.10	Ki	789	nM	GLUTAMIC ACID
5.96	Ki	1100	nM	CHEMBL5173718
5.92	Ki	1190	nM	CHEMBL5209119
5.92	Ki	1200	nM	CHEMBL82375
5.85	Ki	1400	nM	CHEMBL67828
5.85	Ki	1400	nM	CHEMBL429540
5.82	Ki	1500	nM	CHEMBL12448
5.78	Ki	1670	nM	CHEMBL12989
5.60	Ki	2500	nM	CHEMBL305534
5.58	Ki	2600	nM	NBQX
5.58	Ki	2600	nM	CHEMBL12761
5.57	IC50	2700	nM	CHEMBL86313
5.54	IC50	2900	nM	DNQX
5.54	Ki	2910	nM	CHEMBL5206048
5.48	Ki	3300	nM	CHEMBL275334
5.47	Ki	3400	nM	CHEMBL12510
5.44	Ki	3600	nM	CHEMBL309831
5.40	IC50	4000	nM	CHEMBL372797
5.39	Ki	4100	nM	CHEMBL293613
5.32	Ki	4800	nM	CHEMBL12358
5.32	Ki	4800	nM	YM-90K
5.31	IC50	4900	nM	CHEMBL310897
5.31	Ki	4900	nM	CHEMBL12730
5.30	Ki	5000	nM	CHEMBL79454
5.28	Ki	5200	nM	CHEMBL305534
5.24	Ki	5730	nM	CHEMBL51660
5.24	Ki	5700	nM	CHEMBL314248
5.24	Ki	5700	nM	CHEMBL303415
5.23	Ki	5900	nM	CHEMBL293613
5.18	Ki	6600	nM	CHEMBL5208673
5.17	Ki	6700	nM	CHEMBL310503
5.10	IC50	8000	nM	NBQX
5.07	Ki	8500	nM	CHEMBL99012
5.05	Ki	8900	nM	CHEMBL1234118

PubChem BioAssay actives

30 with measured affinity, of 83 total; 26 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3S,4S)-4-[(2Z,4E,6R)-6-carboxyhepta-2,4-dien-2-yl]-3-(carboxymethyl)pyrrolidine-2-carboxylic acid	2114775: Displacement of [3H](2S, 4R)-4-MeGlu (SYM-2081) from GluK3 (unknown origin)	ki	0.0048	uM
(2S,3S,4S)-3-(carboxymethyl)-4-prop-1-en-2-ylpyrrolidine-2-carboxylic acid	93407: Ability to bind to Ionotropic glutamate receptor ionotropic kainate 3 was evaluated	ki	0.0100	uM
(2S,4R)-2-amino-4-[(E)-3-(2-methoxyphenyl)prop-2-enyl]pentanedioic acid	93409: Compound was tested for binding affinity against human Ionotropic glutamate receptor ionotropic kainate 3 in HEK293 cells using [3H]kainate as radioligand	ki	0.0420	uM
2-[7-[3-[[(4-nitrophenyl)carbamoylamino]methyl]pyrrol-1-yl]-2,3-dioxo-6-(trifluoromethyl)-4H-quinoxalin-1-yl]acetic acid	75680: Binding affinity towards cloned human GluR7 subunit stably expressed in cultured HEK293 cells using [3]H-kainate as radioligand	ki	0.0460	uM
N-[7-fluoro-2,3-dioxo-6-(trifluoromethyl)-4H-quinoxalin-1-yl]-2-hydroxybenzamide	1859140: Binding affinity to GluK3 receptor (unknown origin)	ki	0.1420	uM
(2S,4R)-2-amino-4-[(E)-3-(4-chlorophenyl)prop-2-enyl]pentanedioic acid	93407: Ability to bind to Ionotropic glutamate receptor ionotropic kainate 3 was evaluated	ki	0.4230	uM
(2S,4E)-2-amino-4-(2-methylpropylidene)pentanedioic acid	93408: Binding affinity of compound was determined against Ionotropic glutamate receptor ionotropic kainate 3 using cell membranes prepared from HEK293 cells	ki	0.5180	uM
2-[6-nitro-2,3-dioxo-7-[3-[(4-phenylpiperidin-1-yl)methyl]pyrrol-1-yl]-4H-quinoxalin-1-yl]acetic acid	75680: Binding affinity towards cloned human GluR7 subunit stably expressed in cultured HEK293 cells using [3]H-kainate as radioligand	ki	0.5300	uM
(2S,4R)-2-amino-4-[(E)-3-naphthalen-2-ylprop-2-enyl]pentanedioic acid	93407: Ability to bind to Ionotropic glutamate receptor ionotropic kainate 3 was evaluated	ki	0.6170	uM
2-[7-[3-[(4-benzylpiperazin-1-yl)methyl]pyrrol-1-yl]-6-nitro-2,3-dioxo-4H-quinoxalin-1-yl]acetic acid	75680: Binding affinity towards cloned human GluR7 subunit stably expressed in cultured HEK293 cells using [3]H-kainate as radioligand	ki	0.6800	uM
glutamic acid	93407: Ability to bind to Ionotropic glutamate receptor ionotropic kainate 3 was evaluated	ki	0.7890	uM
N-[6-(4-hydroxybut-1-ynyl)-2,3-dioxo-4H-quinoxalin-1-yl]benzamide	1859140: Binding affinity to GluK3 receptor (unknown origin)	ki	1.1000	uM
N-[6-(3-hydroxyprop-1-ynyl)-2,3-dioxo-4H-quinoxalin-1-yl]benzamide	1859140: Binding affinity to GluK3 receptor (unknown origin)	ki	1.1900	uM
2-[6-nitro-2,3-dioxo-7-[3-[(3-phenylpropylamino)methyl]pyrrol-1-yl]-4H-quinoxalin-1-yl]acetic acid	75680: Binding affinity towards cloned human GluR7 subunit stably expressed in cultured HEK293 cells using [3]H-kainate as radioligand	ki	1.4000	uM
2-[6-nitro-2,3-dioxo-7-[3-[[4-(2-phenylethyl)piperazin-1-yl]methyl]pyrrol-1-yl]-4H-quinoxalin-1-yl]acetic acid	75680: Binding affinity towards cloned human GluR7 subunit stably expressed in cultured HEK293 cells using [3]H-kainate as radioligand	ki	1.4000	uM
3-(6-nitro-2,3-dioxo-7-pyrrol-1-yl-4H-quinoxalin-1-yl)propanoic acid	75680: Binding affinity towards cloned human GluR7 subunit stably expressed in cultured HEK293 cells using [3]H-kainate as radioligand	ki	2.5000	uM
[(1S)-1-[(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]ethyl]phosphonic acid	95024: Compound has been evaluated for its binding affinity towards kainate by displacing the radioligand [3H]kainate	ic50	2.7000	uM
N-[2,3-dioxo-6-(2-phenylethynyl)-4H-quinoxalin-1-yl]benzamide	1859140: Binding affinity to GluK3 receptor (unknown origin)	ki	2.9100	uM
2-[[3-[(2S)-2-amino-2-carboxyethyl]-2,6-dioxopyrimidin-1-yl]methyl]benzoic acid	1325321: Antagonist activity at recombinant GluK3 receptor (unknown origin) expressed in Xenopus oocyte assessed as inhibition of glutamate-induced current amplitude by voltage-clamp method	ic50	4.0000	uM
1-[4-(carboxymethyl)-7-nitro-2,3-dioxo-1H-quinoxalin-6-yl]pyrrole-3-carboxylic acid	75680: Binding affinity towards cloned human GluR7 subunit stably expressed in cultured HEK293 cells using [3]H-kainate as radioligand	ki	4.1000	uM
2-amino-3-[3-oxo-5-(1,3-thiazol-2-yl)-1,2-oxazol-4-yl]propanoic acid	91459: In vitro binding affinity against Ionotropic glutamate receptor kainate (kainic acid) using [3H]KAIN as radioligand	ic50	4.9000	uM
2-[6-nitro-2,3-dioxo-7-[3-(piperidin-1-ylmethyl)pyrrol-1-yl]-4H-quinoxalin-1-yl]acetic acid	75680: Binding affinity towards cloned human GluR7 subunit stably expressed in cultured HEK293 cells using [3]H-kainate as radioligand	ki	5.7000	uM
(2S)-2-amino-4-cyclopentylidenepentanedioic acid	93408: Binding affinity of compound was determined against Ionotropic glutamate receptor ionotropic kainate 3 using cell membranes prepared from HEK293 cells	ki	5.7300	uM
4-(2,3-dioxo-1,4-dihydroquinoxalin-6-yl)benzoic acid	1859140: Binding affinity to GluK3 receptor (unknown origin)	ki	6.6000	uM
2-[(E)-2-(2,3-dioxo-1,4-dihydroquinoxalin-6-yl)ethenyl]benzoic acid	1859140: Binding affinity to GluK3 receptor (unknown origin)	ki	8.9000	uM
(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoropyrrolidin-1-yl]methyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid	1434142: Inhibition of GluK3 (unknown origin)	ki	8.9000	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression, increases methylation	5
trichostatin A	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	increases methylation, increases mutagenesis, decreases methylation	2
selenomethylselenocysteine	increases expression	1
methylmercuric chloride	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
terbufos	increases methylation	1
arsenite	increases methylation	1
manganese chloride	increases methylation	1
aflatoxin B2	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
Arsenic Trioxide	decreases expression	1
Vorinostat	affects cotreatment, decreases expression	1
Arsenic	affects methylation	1
Calcitriol	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Fonofos	increases methylation	1
Estradiol	increases expression	1
Ivermectin	decreases expression	1
Methotrexate	decreases expression	1
Parathion	increases methylation	1
Phenylmercuric Acetate	decreases expression	1
Testosterone	decreases expression	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

38 unique, capped per target: 36 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6140042	Binding	Inhibition of kainate receptor (unknown origin) expressed in Xenopus oocytes at 5 uM by radioligand binding assay	Thienopyrimidinone Derivatives as a GluN2B/C/D Biased, Positive Allosteric Modulator of the N-Methyl-d-Aspartate Receptor. — J Med Chem
CHEMBL1954492	Functional	Antagonist activity at human recombinant GluK3 receptor expressed in human HEK293 cells assessed as inhibition of glutamate-stimulated calcium influx by fluorescence assay	Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors. — J Med Chem

Clinical trials (associated diseases)

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