GRIA3

Summary

GRIA3 (glutamate ionotropic receptor AMPA type subunit 3, HGNC:4573) is a protein-coding gene on chromosome Xq25, encoding Glutamate receptor 3 (P42263). Ionotropic glutamate receptor that functions as a ligand-gated cation channel, gated by L-glutamate and glutamatergic agonists such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), quisqualic acid, and kainic acid.

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes composed of multiple subunits, arranged to form ligand-gated ion channels. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. The subunit encoded by this gene belongs to a family of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive glutamate receptors, and is subject to RNA editing (AGA->GGA; R->G). Alternative splicing at this locus results in different isoforms, which may vary in their signal transduction properties.

Source: NCBI Gene 2892 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 763 total — 20 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 69
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_007325

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4573
Approved symbol	GRIA3
Name	glutamate ionotropic receptor AMPA type subunit 3
Location	Xq25
Locus type	gene with protein product
Status	Approved
Aliases	GluA3, GLURC, MRX94, GluR-3, GluR-C, GluR-K3, iGluR3
Ensembl gene	ENSG00000125675
Ensembl biotype	protein_coding
OMIM	305915
Entrez	2892

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000460123, ENST00000477389, ENST00000479118, ENST00000611689, ENST00000616590, ENST00000620443, ENST00000620581, ENST00000622768, ENST00000897928, ENST00000897929, ENST00000970336

RefSeq mRNA: 3 — MANE Select: NM_007325 NM_000828, NM_001256743, NM_007325

CCDS: CCDS14604, CCDS14605, CCDS76017

Canonical transcript exons

ENST00000620443 — 16 exons

Exon	Start	End
ENSE00000675838	123354910	123354963
ENSE00000675927	123402994	123403098
ENSE00000675943	123403412	123403519
ENSE00000675999	123404708	123404914
ENSE00000857614	123398636	123398803
ENSE00000857615	123394968	123395129
ENSE00000857617	123326026	123326213
ENSE00000857618	123253303	123253542
ENSE00002272696	123417402	123417778
ENSE00003461071	123185832	123185990
ENSE00003717122	123488713	123490915
ENSE00003729601	123427941	123428139
ENSE00003733300	123464865	123465112
ENSE00003737305	123482799	123483046
ENSE00003753195	123480063	123480177
ENSE00003851148	123184278	123184644

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 99.28.

FANTOM5 (CAGE): breadth broad, TPM avg 5.1050 / max 717.6807, expressed in 640 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197449	1.8439	324
197450	0.8815	297
197453	0.6897	137
197448	0.4516	157
197452	0.3649	129
197451	0.3616	140
209798	0.2728	83
197447	0.2062	115
197454	0.0329	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.28	gold quality
middle temporal gyrus	UBERON:0002771	97.98	gold quality
primary visual cortex	UBERON:0002436	96.21	gold quality
entorhinal cortex	UBERON:0002728	95.97	gold quality
postcentral gyrus	UBERON:0002581	95.60	gold quality
superior frontal gyrus	UBERON:0002661	95.37	gold quality
parietal lobe	UBERON:0001872	95.35	gold quality
cortical plate	UBERON:0005343	94.92	gold quality
occipital lobe	UBERON:0002021	94.56	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.97	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.92	gold quality
right frontal lobe	UBERON:0002810	93.44	gold quality
prefrontal cortex	UBERON:0000451	93.01	gold quality
cerebral cortex	UBERON:0000956	92.78	gold quality
frontal cortex	UBERON:0001870	92.73	gold quality
neocortex	UBERON:0001950	92.43	gold quality
Ammon’s horn	UBERON:0001954	92.20	gold quality
nucleus accumbens	UBERON:0001882	92.04	gold quality
telencephalon	UBERON:0001893	92.02	gold quality
temporal lobe	UBERON:0001871	91.76	gold quality
cingulate cortex	UBERON:0003027	91.07	gold quality
anterior cingulate cortex	UBERON:0009835	90.92	gold quality
ganglionic eminence	UBERON:0004023	90.85	gold quality
putamen	UBERON:0001874	90.41	gold quality
caudate nucleus	UBERON:0001873	90.17	gold quality
endothelial cell	CL:0000115	90.10	gold quality
buccal mucosa cell	CL:0002336	89.97	gold quality
amygdala	UBERON:0001876	89.34	gold quality
stromal cell of endometrium	CL:0002255	89.17	gold quality
forebrain	UBERON:0001890	88.20	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	27.96
E-GEOD-81547	yes	23.23
E-GEOD-93593	yes	15.51
E-GEOD-83139	yes	11.88
E-ENAD-27	yes	8.25
E-ANND-3	yes	6.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

238 targeting GRIA3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-1252-5P	100.00	69.80	2774
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-4262	100.00	73.26	3931
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4789-5P	99.98	70.76	2721

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 35)

• Flip and flop splice variants of AMPA receptor subunits in the spinal cord of amyotrophic lateral sclerosis. (PMID:12125045)
• T lymphocytes from normal individuals, an alloprimed human T cell clone, and human T leukemia (Jurkat) cells all express high levels of GluR3, identical in sequence with brain GluR3. (PMID:12682273)
• This study investigated whether the AMPA receptor subunit content (GluR1, GluR2, GluR2/3) within “vulnerable” vs. “resistant” sectors of the hippocampus is quantitatively altered with increasing Alzheimer Disease neuropathology (PMID:15144856)
• cell loss and up-regulation of glutamate receptor subunits appear early in temporal lobe epilepsy and contribute to the synaptic plasticity that may facilitate the subsequent sprouting of mossy fiber collaterals (PMID:15145077)
• cleavage and release to the extracellular milieu of the GluR3B peptide may in principle increase its antigenicity (PMID:17202328)
• study provides the genetic and functional evidence that mutant iGluR3 with altered kinetic properties is associated with moderate cognitive impairment in humans (PMID:17989220)
• Of the three AMPA genes analyzed here, only GRIA3 seems to be involved in the pathogenesis of schizophrenia, but only in females. (PMID:18163426)
• results support the involvement of genes GRIA3 and GRIK2 in antidepressant treatment-emergent suicidal ideation (PMID:18593792)
• Aberrant GRIA3 transcripts with multi-exon duplications in a family with X-linked mental retardation are reported. (PMID:19449417)
• The mGlu3 receptor is located on a number of GABAergic interneurons throughout the brain. mGlu3 receptor is one of two primary mGlu receptors that modulate the function of glia. The mGlu3 receptor is present as a postsynaptic receptor as well. (PMID:19933774)
• This study demonistrated that the level of metabotropic glutamate receptor 2/3 is elevated in the prefrontal cortex in patient of major depression disorder. (PMID:19945495)
• AQP3 gene isn’t the responsible gene for this pedigree with auditory neuropathy. (PMID:20564826)
• Two variants in the regulative regions of GRIA1 (rs2195450) and GRIA3 (rs3761555) genes resulted strongly associated with MA (P = 0.00002 and P = 0.0001, respectively), but not associated with MO (PMID:20579352)
• GRIA3 plays a role as a mediator of tumor progression in pancreatic cancer downstream CUX1. (PMID:20689760)
• SNP rs687577 associated with sleep duration and depression risk in Finnish women (PMID:21966062)
• The rs557762 and the TT haplotype in the 11th haplotype block of the GRIA3 gene were associated with feelings of guilt in females. (PMID:22429480)
• the promoter methylation of the GMR2 and GMR5 genes greatly decreased the risk of schizophrenia, and the expression level of the GRM2, GRM5, and GRIA3 genes increased significantly in patients in comparison to healthy controls. (PMID:23149219)
• The ionotrophic glutamate receptors AMPA3 and AMPA3 were decreased in hippocampus in patient with multiple sclerosis. (PMID:23595422)
• An association was observed in migraine patients with the GRIA3 single nucleotide polymorphism rs3761555. (PMID:23772601)
• the levels were comparable for complexes containing GluR2, GluR3 and GluR4 as well as 5-HT1A. Moreover, the levels of complexes containing muscarinic AChR M1, NR1 and GluR1 were significantly increased in male patients with AD. (PMID:24292102)
• The N-terminal domain modulates alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization. (PMID:24652293)
• This study demonstrated that the GRIA3 protein was altered in auditory cortex patient with schizophreia. (PMID:25433904)
• the impaired surface expression of homomeric GluA3 receptors is caused by nonproductive assembly and aggregation to which LBD residues Tyr-454 and Arg-461 strongly contribute. (PMID:26912664)
• This study showed the lower GluA3 mRNA levels in pregnant women. (PMID:28284346)
• Frontotemporal dementia patients manifest significant reduction of the GluR3 subunit in the postsynaptic fraction due to autoantibodies along with increased levels of neuronal Tau. (PMID:28751743)
• Results suggest a role for GluA3 channel activity in the regulation of sleep behavior in both mice and humans. (PMID:29016847)
• Genetic variability in GRIA3 may interact with a functional BDNF polymorphism. (PMID:29338492)
• MicroRNA-330-3p promotes brain metastasis and epithelial-mesenchymal transition via GRIA3 in non-small cell lung cancer. (PMID:31498117)
• The GRIA3 c.2477G > A Variant Causes an Exaggerated Startle Reflex, Chorea, and Multifocal Myoclonus. (PMID:32369665)
• TRAILR1 (rs20576) and GRIA3 (rs12557782) are not associated with interferon-beta response in multiple sclerosis patients. (PMID:33269432)
• X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3. (PMID:34161333)
• Acetylation of H3K27 activated lncRNA NEAT1 and promoted hepatic lipid accumulation in non-alcoholic fatty liver disease via regulating miR-212-5p/GRIA3. (PMID:34652536)
• Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant. (PMID:35031858)
• Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human. (PMID:35697757)
• Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes. (PMID:38038360)

Cross-species orthologs

43 orthologs

Organism	Symbol	Gene ID
danio_rerio	gria3a	ENSDARG00000032737
danio_rerio	gria3b	ENSDARG00000037498
mus_musculus	Gria3	ENSMUSG00000001986
rattus_norvegicus	Gria3	ENSRNOG00000007682
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), GRIK4 (ENSG00000149403), GRID2 (ENSG00000152208), 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 3 — P42263 (reviewed: P42263)

Alternative names: AMPA-selective glutamate receptor 3, GluR-C, GluR-K3, Glutamate receptor ionotropic, AMPA 3

All UniProt accessions (3): P42263, A0A087WYJ6, Q5XKG2

UniProt curated annotations — full annotation on UniProt →

Function. Ionotropic glutamate receptor that functions as a ligand-gated cation channel, gated by L-glutamate and glutamatergic agonists such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), quisqualic acid, and kainic acid. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system and plays an important role in fast excitatory synaptic transmission by inducing long-term potentiation. 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 upon entry of calcium. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.

Subunit / interactions. Homotetramer or heterotetramer of pore-forming glutamate receptor subunits. Tetramers may be formed by the dimerization of dimers. Interacts with PICK1, GRIP1 and GRIP2. Found in a complex with GRIA1, GRIA2, GRIA4, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with CACNG5. Found in a complex with GRIA1, GRIA2, GRIA4, DLG4, CACNG8 and CNIH2.

Subcellular location. Cell membrane. Postsynaptic cell membrane. Postsynaptic density membrane.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Wu type (MRXSW) [MIM:300699] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSW patients have moderate intellectual disability, and additional variable features such as macrocephaly, seizures, myoclonic jerks, autistic behavior, asthenic body habitus, distal muscle weakness and hyporeflexia. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds AMPA (quisqualate) > glutamate > kainate.

Similarity. Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIA3 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P42263-1	Flop	yes
P42263-2	Flip

RefSeq proteins (3): NP_000819, NP_001243672, NP_015564* (*=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 (39 total): sequence variant 7, binding site 6, topological domain 5, glycosylation site 5, transmembrane region 3, modified residue 2, lipid moiety-binding region 2, disulfide bond 2, sequence conflict 2, intramembrane region 2, signal peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42263-F1	83.98	0.51

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): 508; 510; 515; 686; 687; 737

Post-translational modifications (4): 877, 887, 621, 847

Disulfide bonds (2): 91–340, 750–805

Glycosylation sites (5): 63, 266, 380, 415, 422

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-399710	Activation of AMPA receptors
R-HSA-399719	Trafficking of AMPA receptors
R-HSA-416993	Trafficking of GluR2-containing AMPA receptors
R-HSA-438066	Unblocking of NMDA receptors, glutamate binding and activation
R-HSA-8849932	Synaptic adhesion-like molecules

MSigDB gene sets: 509 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, TGCGCANK_UNKNOWN, CCAWYNNGAAR_UNKNOWN, GOMF_GLUTAMATE_GATED_RECEPTOR_ACTIVITY, GOBP_PROTEIN_HOMOTETRAMERIZATION, GGGTGGRR_PAX4_03, GOBP_CELL_CELL_SIGNALING, GTGCCTT_MIR506, GOBP_REGULATION_OF_SYNAPTIC_PLASTICITY, GOBP_PROTEIN_HETEROTETRAMERIZATION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM2, GOBP_REGULATION_OF_POSTSYNAPTIC_MEMBRANE_POTENTIAL, CAATGCA_MIR33, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, HTF_01

GO Biological Process (12): glutamate receptor signaling pathway (GO:0007215), synaptic transmission, glutamatergic (GO:0035249), modulation of chemical synaptic transmission (GO:0050804), protein homotetramerization (GO:0051289), protein heterotetramerization (GO:0051290), long-term synaptic potentiation (GO:0060291), monoatomic ion transport (GO:0006811), 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 (9): amyloid-beta binding (GO:0001540), glutamate-gated receptor activity (GO:0004970), AMPA glutamate receptor activity (GO:0004971), 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 (9): plasma membrane (GO:0005886), endocytic vesicle membrane (GO:0030666), AMPA glutamate receptor complex (GO:0032281), dendritic spine (GO:0043197), postsynaptic membrane (GO:0045211), parallel fiber to Purkinje cell synapse (GO:0098688), postsynaptic density membrane (GO:0098839), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Glutamate binding, activation of AMPA receptors and synaptic plasticity	2
Trafficking of AMPA receptors	1
Activation of NMDA receptors and postsynaptic events	1
Protein-protein interactions at synapses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glutamate-gated receptor activity	3
glutamate receptor activity	2
chemical synaptic transmission	2
protein tetramerization	2
regulation of membrane potential	2
transmitter-gated monoatomic ion channel activity	2
postsynapse	2
cell surface receptor signaling pathway	1
regulation of trans-synaptic signaling	1
protein homooligomerization	1
protein heterooligomerization	1
regulation of synaptic plasticity	1
positive regulation of synaptic transmission	1
transport	1
intracellular signaling cassette	1
monoatomic ion transport	1
transmembrane transport	1
glutamate receptor signaling pathway	1
ligand-gated ion channel signaling pathway	1
peptide binding	1
dicarboxylic acid transmembrane transporter activity	1
amino acid transmembrane transporter activity	1
ionotropic glutamate receptor signaling pathway	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
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic ion channel activity	1
ligand-gated channel activity	1
molecular transducer activity	1
membrane	1
cell periphery	1
endocytic vesicle	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
ionotropic glutamate receptor complex	1
dendrite	1

Protein interactions and networks

STRING

2204 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRIA3	GRIA1	P42261	983
GRIA3	GRIA4	P48058	982
GRIA3	GRIA2	P42262	982
GRIA3	PICK1	Q9NRD5	982
GRIA3	GRIP1	Q9Y3R0	979
GRIA3	CNIH2	Q6PI25	823
GRIA3	CNIH4	Q9P003	815
GRIA3	STXBP1	P61764	774
GRIA3	GSR	P00390	770
GRIA3	GRM5	P41594	754
GRIA3	GRIP2	Q9C0E4	741
GRIA3	CNIH3	Q8TBE1	731
GRIA3	CACNG2	Q9Y698	730
GRIA3	CNIH1	O95406	650
GRIA3	CAMK2A	Q9UQM7	650

IntAct

130 interactions, top by confidence:

A	B	Type	Score
GRIA3	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	GRIA3	psi-mi:“MI:0407”(direct interaction)	0.440
PALS2	GRIA3	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	PTPN13	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	IL16	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	LNX1	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	APBA2	psi-mi:“MI:0407”(direct interaction)	0.440
GRIA3	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (46): GRIA4 (Affinity Capture-MS), HECTD4 (Affinity Capture-MS), GLRB (Affinity Capture-MS), CCPG1 (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), DNAJB9 (Affinity Capture-MS), GLB1L2 (Affinity Capture-MS), SEMA4F (Affinity Capture-MS), FAM69A (Affinity Capture-MS), ALG9 (Affinity Capture-MS), TMPPE (Affinity Capture-MS), LMF2 (Affinity Capture-MS), METAP2 (Affinity Capture-MS), HLA-F (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS)

ESM2 similar proteins: A0A2I4HXH5, A5D6U8, B3A0N5, B6EWW8, E0D877, F8S0Z7, O00462, O35409, P05089, P15693, P19492, P21588, P21589, P29240, P31422, P42263, P49614, P49900, P50635, P52307, P70627, P83456, P83852, Q05927, Q14832, Q1ZZH1, Q29444, Q2KJ64, Q4FZV0, Q561R9, Q5R979, Q5RAL3, Q5RFI5, Q5TVM9, Q5XGR8, Q61503, Q641Z7, Q6AYS4, Q6PCE3, Q8CAA7

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

5 interactions.

A	Effect	B	Mechanism
SHANK3	“up-regulates quantity”	GRIA3	binding
“glutamic acid”	“up-regulates activity”	GRIA3	“chemical activation”
GRIA3	up-regulates	Excitatory_synaptic_transmission
IQSEC2	“up-regulates quantity”	GRIA3	relocalization
GRIA3	“up-regulates quantity”	calcium(2+)	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 84 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
Unblocking of NMDA receptors, glutamate binding and activation	6	59.3×	3e-08
Long-term potentiation	6	51.9×	5e-08
Ras activation upon Ca2+ influx through NMDA receptor	5	51.9×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	49.4×	1e-06
Assembly and cell surface presentation of NMDA receptors	10	46.1×	8e-13
Dopamine Neurotransmitter Release Cycle	5	45.1×	2e-06
Neurexins and neuroligins	11	39.4×	5e-13
Protein-protein interactions at synapses	7	33.8×	5e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	72.6×	3e-14
protein localization to synapse	6	57.5×	8e-08
receptor clustering	7	54.6×	8e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	7	43.4×	3e-08
cell-cell adhesion	10	12.7×	5e-07
protein-containing complex assembly	7	10.0×	3e-04
regulation of small GTPase mediated signal transduction	5	9.0×	5e-03
chemical synaptic transmission	7	6.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	19
Uncertain significance	292
Likely benign	203
Benign	55

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10356	NM_007325.5(GRIA3):c.2497G>A (p.Gly833Arg)	Pathogenic
10357	NM_007325.5(GRIA3):c.1891C>A (p.Arg631Ser)	Pathogenic
10358	NM_007325.5(GRIA3):c.2117T>C (p.Met706Thr)	Pathogenic
10359	NC_000023.11:g.(?123184278)(123490915_?)del	Pathogenic
127195	NM_007325.5(GRIA3):c.1888G>C (p.Gly630Arg)	Pathogenic
1299450	NM_007325.5(GRIA3):c.1979G>C (p.Arg660Thr)	Pathogenic
1334442	NM_007325.5(GRIA3):c.2038_2040delinsTGT (p.Gly680Cys)	Pathogenic
1344571	NM_007325.5(GRIA3):c.1844C>T (p.Ala615Val)	Pathogenic
145141	GRCh38/hg38 Xq25(chrX:123473778-123593934)x2	Pathogenic
1685862	NM_007325.5(GRIA3):c.1450_1453dup (p.Pro485fs)	Pathogenic
1764249	NM_007325.5(GRIA3):c.1266del (p.Arg423fs)	Pathogenic
2064199	NM_007325.5(GRIA3):c.1982T>C (p.Met661Thr)	Pathogenic
2500994	NM_007325.5(GRIA3):c.1957G>T (p.Ala653Ser)	Pathogenic
2685007	GRCh37/hg19 Xq24-25(chrX:120750703-124254005)x3	Pathogenic
2832255	NM_007325.5(GRIA3):c.1564dup (p.Ser522fs)	Pathogenic
3024301	NM_000828.5(GRIA3):c.2359G>A (p.Glu787Lys)	Pathogenic
3246418	NC_000023.10:g.(?122617542)(123834035_?)dup	Pathogenic
3391179	NM_007325.5(GRIA3):c.2359G>A (p.Glu787Lys)	Pathogenic
431114	NM_007325.5(GRIA3):c.1964T>C (p.Phe655Ser)	Pathogenic
980321	GRCh37/hg19 Xq25(chrX:122338834-123471785)x2	Pathogenic
1184928	NM_007325.5(GRIA3):c.1672del (p.Cys558fs)	Likely pathogenic
1331660	NM_007325.5(GRIA3):c.1358G>A (p.Gly453Asp)	Likely pathogenic
1786997	NM_007325.5(GRIA3):c.2167_2175del (p.Ala723_Val725del)	Likely pathogenic
2500995	NM_007325.5(GRIA3):c.1973T>C (p.Val658Ala)	Likely pathogenic
2506483	NM_007325.5(GRIA3):c.307G>T (p.Gly103Ter)	Likely pathogenic
3026632	NM_007325.5(GRIA3):c.2097C>G (p.Tyr699Ter)	Likely pathogenic
3030511	NM_000828.5(GRIA3):c.2396G>T (p.Trp799Leu)	Likely pathogenic
3075673	NM_007325.5(GRIA3):c.1170_1173del (p.Ser391fs)	Likely pathogenic
3236820	NM_007325.5(GRIA3):c.1373T>C (p.Leu458Pro)	Likely pathogenic
3342162	NM_007325.5(GRIA3):c.2077-1G>C	Likely pathogenic

SpliceAI

3607 predictions. Top by Δscore:

Variant	Effect	Δscore
X:123184641:ATAGG:A	donor_loss	1.0000
X:123184642:TAGGT:T	donor_loss	1.0000
X:123184643:AGG:A	donor_loss	1.0000
X:123184646:T:A	donor_loss	1.0000
X:123185826:TTATA:T	acceptor_loss	1.0000
X:123185827:TATAG:T	acceptor_loss	1.0000
X:123185829:TAG:T	acceptor_loss	1.0000
X:123185986:TGCTT:T	donor_gain	1.0000
X:123185987:GCTT:G	donor_gain	1.0000
X:123185987:GCTTG:G	donor_gain	1.0000
X:123185988:CTT:C	donor_gain	1.0000
X:123185989:TT:T	donor_gain	1.0000
X:123185990:TG:T	donor_loss	1.0000
X:123185991:G:GG	donor_gain	1.0000
X:123185992:TAA:T	donor_loss	1.0000
X:123253301:A:AG	acceptor_gain	1.0000
X:123253301:AGTCT:A	acceptor_gain	1.0000
X:123253302:G:GG	acceptor_gain	1.0000
X:123253302:GT:G	acceptor_gain	1.0000
X:123253302:GTC:G	acceptor_gain	1.0000
X:123253302:GTCT:G	acceptor_gain	1.0000
X:123253302:GTCTG:G	acceptor_gain	1.0000
X:123253539:CGAGG:C	donor_loss	1.0000
X:123253541:AGG:A	donor_loss	1.0000
X:123326022:TCAG:T	acceptor_loss	1.0000
X:123326023:CAGG:C	acceptor_loss	1.0000
X:123326024:A:AG	acceptor_gain	1.0000
X:123326024:AG:A	acceptor_gain	1.0000
X:123326025:G:A	acceptor_gain	1.0000
X:123326025:G:GC	acceptor_gain	1.0000

AlphaMissense

5906 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:123185832:G:A	G37D	1.000
X:123185834:G:A	G38R	1.000
X:123185834:G:C	G38R	1.000
X:123185835:G:A	G38E	1.000
X:123185972:T:C	F84L	1.000
X:123185973:T:G	F84C	1.000
X:123185974:T:A	F84L	1.000
X:123185974:T:G	F84L	1.000
X:123253305:T:A	C91S	1.000
X:123253305:T:C	C91R	1.000
X:123253306:G:A	C91Y	1.000
X:123253306:G:C	C91S	1.000
X:123253306:G:T	C91F	1.000
X:123253307:C:G	C91W	1.000
X:123253341:G:A	G103R	1.000
X:123253341:G:C	G103R	1.000
X:123253342:G:A	G103E	1.000
X:123253385:T:G	C117W	1.000
X:123253393:T:C	L120P	1.000
X:123253506:T:A	W158R	1.000
X:123253506:T:C	W158R	1.000
X:123326038:T:C	L174P	1.000
X:123398657:G:C	D312H	1.000
X:123398657:G:T	D312Y	1.000
X:123398658:A:C	D312A	1.000
X:123398658:A:T	D312V	1.000
X:123398660:G:C	A313P	1.000
X:123398681:G:C	A320P	1.000
X:123398694:T:C	L324P	1.000
X:123398741:T:A	C340S	1.000

dbSNP variants (sampled 300 via entrez): RS1000008999 (X:123457939 G>A,C), RS1000011071 (X:123268308 CTT>C), RS1000038331 (X:123419921 G>A,T), RS1000041532 (X:123324551 A>C), RS1000047664 (X:123188209 T>C), RS1000050335 (X:123429713 T>A,C), RS1000053881 (X:123334421 A>C), RS1000055782 (X:123390077 T>C), RS1000079505 (X:123337298 G>A), RS1000091724 (X:123420509 A>T), RS1000128405 (X:123263223 A>G), RS1000135997 (X:123323891 T>C), RS1000145939 (X:123429981 G>A), RS1000160138 (X:123334182 G>A), RS1000167679 (X:123248124 G>A)

Disease associations

OMIM: gene MIM:305915 | disease phenotypes: MIM:300699

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic X-linked intellectual disability 94	Definitive	X-linked
X-linked complex neurodevelopmental disorder	Definitive	X-linked
X-linked intellectual disability due to GRIA3 anomalies	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (8): syndromic X-linked intellectual disability 94 (MONDO:0010402), developmental and epileptic encephalopathy (MONDO:0100620), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), dystonic disorder (MONDO:0003441), neurodegenerative disease (MONDO:0005559), X-linked complex neurodevelopmental disorder (MONDO:0100148), (MONDO:0018222)

Orphanet (2): X-linked intellectual disability due to GRIA3 mutations (Orphanet:364028), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

69 total (30 of 69 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000126	Hydronephrosis
HP:0000188	Short upper lip
HP:0000189	Narrow palate
HP:0000194	Open mouth
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000297	Facial hypotonia
HP:0000303	Mandibular prognathia
HP:0000322	Short philtrum
HP:0000336	Prominent supraorbital ridges
HP:0000400	Macrotia
HP:0000490	Deeply set eye
HP:0000508	Ptosis
HP:0000675	Macrodontia of permanent maxillary central incisor
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000742	Self-mutilation
HP:0000750	Delayed speech and language development
HP:0000817	Reduced eye contact
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003817_15	Mortality in sepsis	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004352	mortality

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D020821	Dystonic Disorders	C10.228.662.300
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D019636	Neurodegenerative Diseases	C10.574
D065886	Neurodevelopmental Disorders	F03.625
C567479	Mental Retardation, X-Linked 94 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2096670 (PROTEIN COMPLEX GROUP), CHEMBL3595 (SINGLE PROTEIN), CHEMBL3883291 (PROTEIN COMPLEX), CHEMBL3885581 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 953,648 (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
CHEMBL1214124	PERAMPANEL	4	1,558
CHEMBL61593	CYCLOTHIAZIDE	4	4,410
CHEMBL575060	GLUTAMIC ACID	3	929,756
CHEMBL14935	TEZAMPANEL ANHYDROUS	2	106
CHEMBL39664	SELFOTEL	2	2,588
CHEMBL275040	KAINIC ACID	2	15,084
CHEMBL1276138	FARAMPATOR	2	146

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3761554	Efficacy	3	antidepressants;Selective serotonin reuptake inhibitors;venlafaxine	Major Depressive Disorder
rs3761555	Efficacy	3	antidepressants;Selective serotonin reuptake inhibitors;venlafaxine	Major Depressive Disorder
rs4825476	Toxicity	3	citalopram	Depression;Suicide
rs502434	Efficacy	3	antidepressants;Selective serotonin reuptake inhibitors;venlafaxine	Major Depressive Disorder

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs502434	GRIA3	3	2.50	1	antidepressants;Selective serotonin reuptake inhibitors;venlafaxine
rs3761554	GRIA3	3	2.50	1	antidepressants;Selective serotonin reuptake inhibitors;venlafaxine
rs3761555	GRIA3	3	2.50	1	antidepressants;Selective serotonin reuptake inhibitors;venlafaxine
rs4825476	GRIA3	3	3.00	1	citalopram

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — Ionotropic glutamate receptors

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
LY404187	Positive	5.78	pEC50
LY392098	Positive	5.72	pEC50
cyclothiazide	Positive	4.86	pEC50

Binding affinities (BindingDB)

12 measured of 19 human assays (20 total across all organisms); most potent 12 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
(RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionicacid	KI	12 nM
(S)-5-Fluorowillardiine	KI	179 nM
3-Hydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxalin-2-ol anion	KI	310 nM
Dnal,Cys,Tyr,DTrp,Lys,Val,Cys,Nal-nh2	KI	494 nM
SR 147778	KI	1000 nM
NS257	KI	1430 nM
glutamate-AMPA	KI	1490 nM
NSC_3140	KI	1660 nM
CAS_3035216	KI	1960 nM
7-Cyano-3-hydroxy-6-nitro-quinoxalin-2-ol anion	KI	2110 nM
Digensaeure	KI	2630 nM
(2S,3S,4S)-2-CARBOXY-4-[(1Z,3E,5R)-5-CARBOXY-1-METHYL-1,3-HEXADIENYL]-3-PYRROLIDINEACETIC ACID	KI	2770 nM

ChEMBL bioactivities

199 potent at pChembl≥5 of 260 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.65	Ki	2.24	nM	CHEMBL370038
8.40	Ki	4	nM	CHEMBL12696
8.40	Ki	4	nM	CHEMBL84142
8.40	Ki	4	nM	CHEMBL82375
8.30	Ki	5	nM	CHEMBL13076
8.30	Ki	5	nM	CHEMBL273675
8.15	Ki	7	nM	CHEMBL309831
7.82	Ki	15	nM	CHEMBL12510
7.80	Ki	16	nM	CHEMBL188018
7.72	Ki	19	nM	CHEMBL90251
7.72	IC50	19	nM	(R,S)-AMPA
7.70	Ki	20	nM	CHEMBL5192550
7.70	Ki	20	nM	CHEMBL310503
7.69	Ki	20.6	nM	(S)-AMPA
7.68	Ki	21	nM	(R,S)-AMPA
7.66	Ki	22	nM	CHEMBL116565
7.66	Ki	22	nM	CHEMBL293613
7.64	IC50	23	nM	(R,S)-AMPA
7.52	IC50	30	nM	CHEMBL94859
7.52	IC50	30	nM	JORO SPIDER TOXIN 3
7.40	IC50	40	nM	(R,S)-AMPA
7.35	Ki	44.8	nM	CHEMBL370941
7.31	Ki	49	nM	CHEMBL12989
7.28	IC50	52	nM	NBQX
7.27	Ki	54	nM	CHEMBL79348
7.24	Ki	57	nM	CHEMBL5199485
7.22	Ki	60	nM	CHEMBL79454
7.20	IC50	63	nM	CHEMBL293206
7.18	Ki	66	nM	CHEMBL5209014
7.18	Ki	66	nM	CHEMBL314248
7.17	Ki	68	nM	CHEMBL93649
7.16	Ki	70	nM	NBQX
7.16	Ki	70	nM	CHEMBL268284
7.15	Ki	71	nM	CHEMBL12761
7.13	Ki	74	nM	CHEMBL274588
7.12	Ki	76	nM	CHEMBL12358
7.11	Ki	78	nM	CHEMBL275334
7.10	IC50	80	nM	CHEMBL293206
7.08	Ki	84	nM	YM-90K
7.03	IC50	94	nM	CHEMBL310897
7.02	Ki	95	nM	CHEMBL13018
6.96	Ki	110	nM	CHEMBL418535
6.89	IC50	130	nM	CHEMBL104208
6.87	Ki	135	nM	YM-90K
6.85	IC50	140	nM	CHEMBL431382
6.85	Ki	140	nM	CHEMBL27653
6.85	Ki	140	nM	TQX-173
6.85	Ki	140	nM	CHEMBL427734
6.85	IC50	140	nM	CHEMBL75761
6.85	Ki	140	nM	CHEMBL8829

PubChem BioAssay actives

131 with measured affinity, of 370 total; 50 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)-2-amino-3-[5-(2-methyltetrazol-5-yl)-3-oxo-1,2-oxazol-4-yl]propanoic acid	239017: Binding affinity for ionotropic Glutamate receptor AMPA 3 expressed in Sf9 cells	ki	0.0022	uM
7-[4-[(4-carboxyphenyl)carbamoyloxymethyl]imidazol-1-yl]-3-oxo-6-(trifluoromethyl)-4H-quinoxaline-2-carboxylic acid	1859131: Binding affinity to AMPA receptor (unknown origin)	ki	0.0160	uM
8-(3-carboxypyrrol-1-yl)-7-nitro-4-oxo-5H-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylic acid	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.0190	uM
2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid	92807: Inhibition of the binding of radioligand [3H]AMPA in the presence at high-affinity AMPA receptor sites.	ic50	0.0190	uM
3-ethyl-12-imidazol-1-yl-11-nitro-2,5,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(13),3,5,9,11-pentaen-7-one	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.0200	uM
(2S)-2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid	239017: Binding affinity for ionotropic Glutamate receptor AMPA 3 expressed in Sf9 cells	ki	0.0206	uM
7-[4-[(4-carboxyphenyl)carbamoyloxymethyl]imidazol-1-yl]-6-nitro-3-oxo-4H-quinoxaline-2-carboxylic acid	1859131: Binding affinity to AMPA receptor (unknown origin)	ki	0.0220	uM
(2S)-N-[5-[3-[4-(3-aminopropylamino)butylamino]propanoylamino]pentyl]-2-[[2-(2,4-dihydroxyphenyl)acetyl]amino]butanediamide	477265: Inhibition of recombinant GluA3 receptor flop isoform expressed in Xenopus oocytes assessed as inhibition of 300 uM kainate-induced current by patch clamp electrophysiological assay	ic50	0.0300	uM
2-amino-3-[5-(2-methyltetrazol-5-yl)-3-oxo-1,2-oxazol-4-yl]propanoic acid	92806: In vitro binding affinity against Ionotropic glutamate receptor AMPA using [3H]AMPA as radioligand	ic50	0.0300	uM
2-amino-3-[5-(2-ethyltetrazol-5-yl)-3-oxo-1,2-oxazol-4-yl]propanoic acid	239017: Binding affinity for ionotropic Glutamate receptor AMPA 3 expressed in Sf9 cells	ki	0.0448	uM
12-imidazol-1-yl-11-nitro-2,5,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(13),3,5,9,11-pentaen-7-one	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.0570	uM
9-methyl-6-nitro-4,7,8,10-tetrahydro-1H-pyrido[3,4-f]quinoxaline-2,3-dione	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ic50	0.0630	uM
12-imidazol-1-yl-11-(trifluoromethyl)-2,5,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5,10,12-pentaen-7-one	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.0660	uM
1-(2-ethoxycarbonyl-7-nitro-4-oxo-5H-[1,2,4]triazolo[1,5-a]quinoxalin-8-yl)pyrrole-3-carboxylic acid	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.0680	uM
7,8-dichloro-4-oxo-5H-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylic acid	1859124: Displacement of [3H]glycine from AMPA receptor (unknown origin)	ki	0.0740	uM
6-imidazol-1-yl-7-nitro-1,4-dihydroquinoxaline-2,3-dione	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.0840	uM
2-amino-3-[3-oxo-5-(1,3-thiazol-2-yl)-1,2-oxazol-4-yl]propanoic acid	92806: In vitro binding affinity against Ionotropic glutamate receptor AMPA using [3H]AMPA as radioligand	ic50	0.0940	uM
2-amino-3-(3-hydroxy-5-methyltriazol-4-yl)propanoic acid	2071188: Binding affinity to AMPA receptor (unknown origin)	ic50	0.1300	uM
2-[(6-ethyl-7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl-methylamino]acetic acid	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ic50	0.1400	uM
6-imidazol-1-yl-7-nitro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.1400	uM
ethyl 2-[(6-ethyl-7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl-methylamino]acetate	1866051: Antagonist activity at AMPA receptor (unknown origin)	ic50	0.1400	uM
8-chloro-9-(3-formylpyrrol-1-yl)-5-oxo-6H-pyrazolo[1,5-c]quinazoline-2-carboxylic acid	1871553: Binding affinity to AMPA (unknown origin)	ki	0.1400	uM
8-chloro-5-oxo-9-(1,2,4-triazol-4-yl)-6H-pyrazolo[1,5-c]quinazoline-2-carboxylic acid	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.1400	uM
7-chloro-4-oxo-8-(1,2,4-triazol-4-yl)-5H-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylic acid	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.1400	uM
(2S)-2-amino-3-(4-oxo-1,2,5-thiadiazol-3-yl)propanoic acid	320601: Binding affinity at iGluR3o receptor expressed in sf9 cells by radioligand binding assay	ki	0.1600	uM
8,9-dichloro-5-oxo-6H-pyrazolo[1,5-c]quinazoline-2-carboxylic acid	1859124: Displacement of [3H]glycine from AMPA receptor (unknown origin)	ki	0.1600	uM
9-amino-7-chloro-4-oxo-5H-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylic acid	1859124: Displacement of [3H]glycine from AMPA receptor (unknown origin)	ki	0.1600	uM
12-imidazol-1-yl-11-nitro-2,4,5,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(13),3,5,9,11-pentaen-7-one	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.1900	uM
7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile	1859129: Displacement of [3H]CNQX from AMPA receptor (unknown origin)	ic50	0.2000	uM
(2S)-N-[5-[3-[3-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]propylamino]propylamino]pentyl]-2-[[2-(2,4-dihydroxyphenyl)acetyl]amino]butanediamide	477274: Inhibition of recombinant GluA3 receptor flip isoform expressed in Xenopus oocytes assessed as inhibition of 100 uM kainate-induced current by patch clamp electrophysiological assay	ic50	0.2300	uM
4-cyclopropyl-7-fluoro-2,3-dihydro-1lambda6,2,4-benzothiadiazine 1,1-dioxide	2034047: Positive allosteric modulation at AMPAR in HEK293 cells expressing GluA2Q assessed as glutamate induced calcium influx	ec50	0.2754	uM
6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione	92045: Inhibition of Ionotropic glutamate receptor AMPA binding to human hippocampal homogenates at concentration of 5-7 uM	ic50	0.2800	uM
4-cyclopropyl-7-fluoro-2-(fluoromethyl)-3H-1lambda6,2,4-benzothiadiazine 1,1-dioxide	2034047: Positive allosteric modulation at AMPAR in HEK293 cells expressing GluA2Q assessed as glutamate induced calcium influx	ec50	0.2818	uM
8-methyl-6-nitro-4,7,9,10-tetrahydro-1H-pyrido[4,3-f]quinoxaline-2,3-dione	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ic50	0.2900	uM
[(1S)-1-[(7-iodo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]ethyl]phosphonic acid	92802: Compound has been evaluated for its binding affinity towards Ionotropic glutamate receptor AMPA by displacing the radioligand [3H]AMPA	ic50	0.3400	uM
glutamic acid	2071206: Binding affinity to AMPA receptor (unknown origin) assessed as inhibition constant	ki	0.3400	uM
7-chloro-4-oxo-9-(1,2,4-triazol-4-yl)-5H-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylic acid	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.4000	uM
6-bromo-9-butan-2-yl-4,7,8,10-tetrahydro-1H-pyrido[3,4-f]quinoxaline-2,3-dione	1859123: Displacement of [3H]kainate from AMPA receptor (unknown origin)	ic50	0.4300	uM
2-[(E)-2-(2,3-dioxo-1,4-dihydroquinoxalin-6-yl)ethenyl]benzoic acid	1859131: Binding affinity to AMPA receptor (unknown origin)	ic50	0.4800	uM
7-chloro-8-(3-formylpyrrol-1-yl)-4-oxo-5H-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylic acid	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.5300	uM
1,1,1-trifluoro-N-(7-nitro-2-oxo-1H-quinolin-3-yl)methanesulfonamide	92933: Binding affinity against Ionotropic glutamate receptor AMPA using [3H]AMPA as a radioligand	ki	0.6000	uM
6-bromo-9-(3-methylbutyl)-4,7,8,10-tetrahydro-1H-pyrido[3,4-f]quinoxaline-2,3-dione	1859123: Displacement of [3H]kainate from AMPA receptor (unknown origin)	ic50	0.6800	uM
2-amino-3-(2,3-dioxo-4H-quinoxalin-1-yl)propanoic acid	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ic50	0.6900	uM
2-amino-3-[5-(1-methyl-1,2,4-triazol-3-yl)-3-oxo-1,2-oxazol-4-yl]propanoic acid	92806: In vitro binding affinity against Ionotropic glutamate receptor AMPA using [3H]AMPA as radioligand	ic50	0.7000	uM
2-(6,7-dimethyl-2,3-dioxo-4H-quinoxalin-1-yl)acetic acid	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.7000	uM
7-chloro-4-cyclopropyl-2,3-dihydro-1lambda6,2,4-benzothiadiazine 1,1-dioxide	2034047: Positive allosteric modulation at AMPAR in HEK293 cells expressing GluA2Q assessed as glutamate induced calcium influx	ec50	0.7943	uM
7,8-dichloro-1-propyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-one	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ic50	0.8300	uM
7-chloro-4-oxo-8-pyrrol-1-yl-5H-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylic acid	1859112: Displacement of [3H]AMPA from AMPA receptor (unknown origin)	ki	0.8600	uM
6-nitro-2,3-dioxo-1,4-dihydrobenzo[f]quinoxaline-7-sulfonamide	93101: Ability to displace binding of [3H]AMPA to recombinant human Ionotropic glutamate receptor AMPA 3	ki	0.9000	uM
N-[7-fluoro-2,3-dioxo-6-(trifluoromethyl)-4H-quinoxalin-1-yl]-2-hydroxybenzamide	1859131: Binding affinity to AMPA receptor (unknown origin)	ki	0.9600	uM

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	5
mercuric bromide	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
Tretinoin	increases expression, decreases expression	2
Aflatoxin B1	increases expression, decreases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
ascorbate-2-phosphate	increases expression, affects binding, affects cotreatment	1
trichostatin A	decreases expression, increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	increases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression, decreases expression	1
CGP 52608	affects binding, increases reaction	1
Chir 99021	affects cotreatment, increases expression, affects binding	1
belinostat	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	increases expression, affects cotreatment	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases expression	1
Fulvestrant	decreases methylation	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

126 unique, capped per target: 113 binding, 13 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5114182	Binding	Displacement of [3H]AMPA from AMPA receptor (unknown origin)	Functionalized quinoxalinones as privileged structures with broad-ranging pharmacological activities. — Eur J Med Chem
CHEMBL702514	Functional	Compound was evaluated to potentiate response of AMPA-activated current in Xenopus oocytes expressing Ionotropic glutamate receptor AMPA	Enantioselective synthesis of a pyrrolo-benzothiadiazine derivative S 18986, a new AMPA receptor positive modulator — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT04727970	PHASE1	COMPLETED	Tricaprilin Infantile Spasms Pilot Study
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT03876444	PHASE2/PHASE3	UNKNOWN	Intravenous Methylprednisolone Versus Oral Prednisolone for Infantile Spasms
NCT05279118	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Ketogenic Diet vs ACTH for the Treatment of Children With West Syndrome
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT04302116	Not specified	RECRUITING	Vigabatrin With High Dose Prednisolone Combination Therapy vs Vigabatrin Alone for Infantile Spasm