GRIA4

Summary

GRIA4 (glutamate ionotropic receptor AMPA type subunit 4, HGNC:4574) is a protein-coding gene on chromosome 11q22.3, encoding Glutamate receptor 4 (P48058). 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 of this gene results in transcript variants encoding different isoforms, which may vary in their signal transduction properties. Some haplotypes of this gene show a positive association with schizophrenia.

Source: NCBI Gene 2893 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with or without seizures and gait abnormalities (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 260 total — 2 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000829

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4574
Approved symbol	GRIA4
Name	glutamate ionotropic receptor AMPA type subunit 4
Location	11q22.3
Locus type	gene with protein product
Status	Approved
Aliases	GluA4, GLURD, GluR-4, GluR-D, GLUR4C
Ensembl gene	ENSG00000152578
Ensembl biotype	protein_coding
OMIM	138246
Entrez	2893

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000282499, ENST00000393125, ENST00000428631, ENST00000525032, ENST00000525187, ENST00000525921, ENST00000525942, ENST00000527177, ENST00000527669, ENST00000527687, ENST00000530497, ENST00000531011, ENST00000531986, ENST00000533094, ENST00000703743, ENST00000706777, ENST00000936181

RefSeq mRNA: 4 — MANE Select: NM_000829 NM_000829, NM_001077243, NM_001077244, NM_001112812

CCDS: CCDS41706, CCDS41707, CCDS8333

Canonical transcript exons

ENST00000282499 — 17 exons

Exon	Start	End
ENSE00001514240	105610073	105610428
ENSE00002145938	105610908	105611085
ENSE00003485621	105862024	105862208
ENSE00003523754	105752981	105753220
ENSE00003558661	105898269	105898427
ENSE00003563883	105979575	105982090
ENSE00003606509	105887519	105887572
ENSE00003789053	105612276	105612434
ENSE00003888962	105971914	105972028
ENSE00003890287	105918712	105918918
ENSE00003891094	105905197	105905301
ENSE00003892557	105910435	105910545
ENSE00003893445	105926741	105926939
ENSE00003895868	105924399	105924769
ENSE00003896007	105933722	105933969
ENSE00003896079	105903814	105903981
ENSE00003989771	105974310	105974444

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 95.70.

FANTOM5 (CAGE): breadth broad, TPM avg 7.2530 / max 824.4752, expressed in 326 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116487	3.5178	231
116488	1.4562	182
116479	1.1586	186
116478	0.2405	107
116480	0.1918	81
116481	0.1486	71
116476	0.1398	75
116483	0.1038	56
116486	0.1004	49
116477	0.0704	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	95.70	gold quality
cerebellar cortex	UBERON:0002129	95.69	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.15	gold quality
cerebellum	UBERON:0002037	94.56	gold quality
prefrontal cortex	UBERON:0000451	92.32	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.10	gold quality
anterior cingulate cortex	UBERON:0009835	90.17	gold quality
cingulate cortex	UBERON:0003027	90.03	gold quality
cerebellar vermis	UBERON:0004720	89.80	gold quality
right frontal lobe	UBERON:0002810	89.39	gold quality
frontal cortex	UBERON:0001870	89.35	gold quality
frontal lobe	UBERON:0016525	89.35	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.20	gold quality
neocortex	UBERON:0001950	89.07	gold quality
pons	UBERON:0000988	89.03	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.42	gold quality
spinal cord	UBERON:0002240	86.63	gold quality
cerebral cortex	UBERON:0000956	86.61	gold quality
superior frontal gyrus	UBERON:0002661	86.03	gold quality
amygdala	UBERON:0001876	85.96	gold quality
postcentral gyrus	UBERON:0002581	85.91	gold quality
hypothalamus	UBERON:0001898	85.56	gold quality
parietal lobe	UBERON:0001872	85.09	gold quality
superior vestibular nucleus	UBERON:0007227	85.06	gold quality
primary visual cortex	UBERON:0002436	84.73	gold quality
telencephalon	UBERON:0001893	84.35	gold quality
temporal lobe	UBERON:0001871	84.03	gold quality
brain	UBERON:0000955	83.74	gold quality
stromal cell of endometrium	CL:0002255	83.36	gold quality
occipital lobe	UBERON:0002021	83.01	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	636.14
E-GEOD-93593	yes	536.00
E-HCAD-35	yes	101.54
E-MTAB-7316	yes	20.84
E-HCAD-25	yes	19.98
E-GEOD-137537	yes	9.09
E-ANND-3	yes	5.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

116 targeting GRIA4, 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-3163	100.00	77.23	8605
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-513A-5P	100.00	69.77	2465
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-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057

Literature-anchored findings (GeneRIF, showing 23)

• Flip and flop splice variants of AMPA receptor subunits in the spinal cord of amyotrophic lateral sclerosis. (PMID:12125045)
• characterization of homomeric alpha-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA)-selective GluR-D glutamate receptors carrying N-terminal deletions (PMID:12393905)
• Results suggest that at least one susceptibility locus for schizophrenia is located within or very close to the GRIA4 region in Japanese. (PMID:12497607)
• alternative splicing isoform of GluR4, human GluR4c has a 113-bp insert containing a stop codon, resulting in a short C terminus. (PMID:15306133)
• The minimal kinetic mechanism for channel opening is consistent with binding of two glutamate molecules per receptor complex. (PMID:15823042)
• GluR4 may regulate its synaptic targeting through phosphorylation-dependent interactions with alpha-Actinin-1 and IQGAP1 (PMID:16190873)
• The present findings show that the interaction between PKCgamma and GluR4 is specifically required to assure PKC-driven phosphorylation and surface membrane expression of GluR4. (PMID:17233759)
• Of the three AMPA genes analyzed here, only GRIA3 seems to be involved in the pathogenesis of schizophrenia, but only in females. (PMID:18163426)
• Did not observed any significant association between GRIA4 polymorphisms and clinical improvement in patients with Major depressive disorder. (PMID:22057216)
• No significant association GRIA4 polymorphisms was found with the diagnosis of schizophrenia. (PMID:22094384)
• SNPs within GRIA4 may not be associated with the development and treatment outcomes in BD (PMID:22122651)
• The data potentially suggest a lack of epistatic interaction between GRIA2 and GRIA4 variants regarding clinical outcomes in patients with major depressive disorder. (PMID:23613500)
• 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)
• Statistical analysis showed no association between migraine and the GRIA2 and GRIA4 polymorphisms investigated. (PMID:24512576)
• The N-terminal domain modulates alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization. (PMID:24652293)
• Interaction with the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR4. (PMID:24962026)
• This study demonstrated that the GRIA4 protein was altered in auditory cortex patient with schizophreia. (PMID:25433904)
• A transient positive feedback mechanism between AMPAR and stargazin has implications for information processing in the brain, because it should allow activity-dependent facilitation of excitatory synaptic transmission through a postsynaptic mechanism. (PMID:26744192)
• Study shows that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA4 is expressed on oligodendrocytes, myelin and on axons in humans. (PMID:27443784)
• The authors suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features. (PMID:29220673)
• Study identifies glutamate ionotropic receptor GRIA4 as a risk gene for comorbid nicotine dependence and major depression. (PMID:30287806)
• Colorectal cancer promoter methylation alteration affects the expression of glutamate ionotropic receptor AMPA type subunit 4 alternative isoforms potentially relevant in colon tissue. (PMID:34719006)
• Association of SLC12A1 and GLUR4 Ion Transporters with Neoadjuvant Chemoresistance in Luminal Locally Advanced Breast Cancer. (PMID:38003293)

Cross-species orthologs

43 orthologs

Organism	Symbol	Gene ID
danio_rerio	gria4a	ENSDARG00000037496
danio_rerio	gria4b	ENSDARG00000059368
mus_musculus	Gria4	ENSMUSG00000025892
rattus_norvegicus	Gria4	ENSRNOG00000006957
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), 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 4 — P48058 (reviewed: P48058)

Alternative names: AMPA-selective glutamate receptor 4, GluR-D, Glutamate receptor ionotropic, AMPA 4

All UniProt accessions (8): P48058, A0A8D9PH77, A0A994J6J2, E9PJZ5, E9PQY1, E9PR13, G3V164, H0YDL4

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. 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 monovalent and divalent cations such as sodium and 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 L-glutamate.

Subunit / interactions. Homotetramer or heterotetramer of pore-forming glutamate receptor subunits. Tetramers may be formed by the dimerization of dimers. Interacts with EPB41L1 via its C-terminus. Isoform 3 interacts with PICK1. Found in a complex with GRIA1, GRIA2, GRIA3, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with CACNG5 and PRKCG. Found in a complex with GRIA1, GRIA2, GRIA3, DLG4, CACNG8 and CNIH2.

Subcellular location. Cell membrane. Postsynaptic cell membrane. Cell projection. Dendrite.

Post-translational modifications. Palmitoylated. Depalmitoylated upon L-glutamate stimulation. Cys-611 palmitoylation leads to Golgi retention and decreased cell surface expression. In contrast, Cys-837 palmitoylation does not affect cell surface expression but regulates stimulation-dependent endocytosis. Phosphorylated at Ser-862 by PRKCG; phosphorylation increases plasma membrane-associated GRI4 expression.

Disease relevance. Neurodevelopmental disorder with or without seizures and gait abnormalities (NEDSGA) [MIM:617864] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay apparent from infancy or early childhood, mild to profound intellectual disability, hypertonia early in life, which progresses to spasticity and impaired gait later, and behavioral abnormalities. Some patients may develop seizures of variable severity early in life. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The M4 transmembrane segment mediates tetramerization and is required for cell surface expression.

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

Similarity. Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIA4 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P48058-1	1	yes
P48058-2	2

RefSeq proteins (4): NP_000820, NP_001070711, NP_001070712, NP_001106283 (=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), 3 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Mg(2+)(in) = Mg(2+)(out) (RHEA:29827)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (40 total): binding site 6, glycosylation site 6, topological domain 5, sequence variant 5, sequence conflict 4, transmembrane region 3, lipid moiety-binding region 2, disulfide bond 2, splice variant 2, intramembrane region 2, signal peptide 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48058-F1	83.24	0.48

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): 500; 502; 507; 676; 677; 727

Post-translational modifications (3): 862, 611, 837

Disulfide bonds (2): 84–331, 740–795

Glycosylation sites (6): 52, 56, 258, 371, 407, 414

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: 292 (showing top): E2F_Q4, E2F4DP1_01, GOMF_GLUTAMATE_GATED_RECEPTOR_ACTIVITY, chr11q22, TGACCTY_ERR1_Q2, GOBP_CELL_CELL_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_APOPTOTIC_PROCESS, E2F1DP1_01, E2F1DP2_01, GOBP_REGULATION_OF_POSTSYNAPTIC_MEMBRANE_POTENTIAL, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, TGACATY_UNKNOWN, GOBP_SYNAPTIC_SIGNALING, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN

GO Biological Process (9): glutamate receptor signaling pathway (GO:0007215), negative regulation of smooth muscle cell apoptotic process (GO:0034392), synaptic transmission, glutamatergic (GO:0035249), modulation of chemical synaptic transmission (GO:0050804), monoatomic ion transport (GO:0006811), 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), 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), 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), dendrite (GO:0030425), endocytic vesicle membrane (GO:0030666), AMPA glutamate receptor complex (GO:0032281), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), postsynaptic density membrane (GO:0098839), extracellular vesicle (GO:1903561), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

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 receptor activity	2
chemical synaptic transmission	2
glutamate-gated receptor activity	2
regulation of membrane potential	2
transmitter-gated monoatomic ion channel activity	2
postsynapse	2
cellular anatomical structure	2
cell surface receptor signaling pathway	1
negative regulation of muscle cell apoptotic process	1
smooth muscle cell apoptotic process	1
regulation of smooth muscle cell apoptotic process	1
regulation of trans-synaptic signaling	1
transport	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 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
binding	1
monoatomic ion channel activity	1
ligand-gated channel activity	1
molecular transducer activity	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1
endocytic vesicle	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
ionotropic glutamate receptor complex	1
somatodendritic compartment	1

Protein interactions and networks

STRING

2254 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRIA4	GRIA1	P42261	983
GRIA4	GRIA2	P42262	982
GRIA4	GRIA3	P42263	982
GRIA4	GSR	P00390	896
GRIA4	GRM2	Q14416	832
GRIA4	CACNG2	Q9Y698	818
GRIA4	GRM3	Q14832	803
GRIA4	NPTX2	P47972	781
GRIA4	NCDN	Q9UBB6	743
GRIA4	PICK1	Q9NRD5	722
GRIA4	SHISA9	B4DS77	717
GRIA4	GRM7	Q14831	710
GRIA4	CNIH1	O95406	696
GRIA4	GRIP1	Q9Y3R0	664
GRIA4	CNIH2	Q6PI25	650

IntAct

7 interactions, top by confidence:

A	B	Type	Score
GRIA3	SEMA4F	psi-mi:“MI:0914”(association)	0.350
GRIA3	HECTD4	psi-mi:“MI:0914”(association)	0.350
PTBP3		psi-mi:“MI:0914”(association)	0.350
GRIA4	CAMK2A	psi-mi:“MI:0217”(phosphorylation reaction)	0.310
PRKACA	GRIA4	psi-mi:“MI:0217”(phosphorylation reaction)	0.310
GRIA4	PRKACA	psi-mi:“MI:0217”(phosphorylation reaction)	0.310

BioGRID (36): GRIA4 (Affinity Capture-MS), GRIA4 (Affinity Capture-MS), GRIA4 (Synthetic Lethality), GRIA4 (Affinity Capture-Western), GRIA4 (Affinity Capture-Western), GRIA4 (Affinity Capture-Western), EPB41L1 (Reconstituted Complex), CAD (Affinity Capture-MS), MYH10 (Affinity Capture-MS), MYH9 (Affinity Capture-MS), DHX9 (Affinity Capture-MS), GRIA4 (Affinity Capture-MS), TUBB4B (Affinity Capture-MS), TUBA1B (Affinity Capture-MS), SYNCRIP (Affinity Capture-MS)

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

12 interactions.

A	Effect	B	Mechanism
SHANK3	“up-regulates quantity”	GRIA4	binding
“glutamic acid”	“up-regulates activity”	GRIA4	“chemical activation”
GRIA4	up-regulates	Excitatory_synaptic_transmission
IQSEC2	“up-regulates quantity”	GRIA4	relocalization
GRIA4	“up-regulates quantity”	calcium(2+)	relocalization
CAMK2A	up-regulates	GRIA4	phosphorylation
PRKACA	up-regulates	GRIA4	phosphorylation
PRKCA	up-regulates	GRIA4	phosphorylation
PRKCG	up-regulates	GRIA4	phosphorylation
FUS	“down-regulates quantity by repression”	GRIA4	“post transcriptional regulation”
PRKCA	unknown	GRIA4	phosphorylation
CAMK2G	unknown	GRIA4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	7
Uncertain significance	195
Likely benign	32
Benign	7

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1332998	NM_000829.4(GRIA4):c.1918G>T (p.Ala640Ser)	Pathogenic
2500997	NM_000829.4(GRIA4):c.2090G>A (p.Arg697Gln)	Pathogenic
1708272	NM_000829.4(GRIA4):c.1918G>A (p.Ala640Thr)	Likely pathogenic
1708322	NM_000829.4(GRIA4):c.341A>G (p.His114Arg)	Likely pathogenic
3067938	NM_000829.4(GRIA4):c.536G>A (p.Trp179Ter)	Likely pathogenic
446207	NM_000829.4(GRIA4):c.1921A>G (p.Asn641Asp)	Likely pathogenic
446209	NM_000829.4(GRIA4):c.1931C>T (p.Ala644Val)	Likely pathogenic
446210	NM_000829.4(GRIA4):c.2090G>C (p.Arg697Pro)	Likely pathogenic
631525	NM_000829.4(GRIA4):c.2209C>T (p.Arg737Ter)	Likely pathogenic

SpliceAI

4310 predictions. Top by Δscore:

Variant	Effect	Δscore
11:105612430:CGCCT:C	donor_gain	1.0000
11:105612431:GCCT:G	donor_gain	1.0000
11:105612431:GCCTG:G	donor_gain	1.0000
11:105612432:CCT:C	donor_gain	1.0000
11:105612435:G:GG	donor_gain	1.0000
11:105752979:A:AG	acceptor_gain	1.0000
11:105752980:G:GA	acceptor_gain	1.0000
11:105752980:GTCT:G	acceptor_gain	1.0000
11:105852875:A:T	donor_gain	1.0000
11:105862018:CAATA:C	acceptor_loss	1.0000
11:105862021:TAG:T	acceptor_loss	1.0000
11:105862022:A:AG	acceptor_gain	1.0000
11:105862022:AGG:A	acceptor_loss	1.0000
11:105862023:G:GG	acceptor_gain	1.0000
11:105862208:GGT:G	donor_loss	1.0000
11:105862209:G:GG	donor_gain	1.0000
11:105862209:GTA:G	donor_loss	1.0000
11:105862210:T:A	donor_loss	1.0000
11:105898265:ATAG:A	acceptor_gain	1.0000
11:105898265:ATAGG:A	acceptor_gain	1.0000
11:105898267:A:AG	acceptor_gain	1.0000
11:105898267:AG:A	acceptor_gain	1.0000
11:105898267:AGG:A	acceptor_gain	1.0000
11:105898268:G:GG	acceptor_gain	1.0000
11:105898268:GG:G	acceptor_gain	1.0000
11:105898268:GGG:G	acceptor_gain	1.0000
11:105898268:GGGA:G	acceptor_gain	1.0000
11:105898268:GGGAT:G	acceptor_gain	1.0000
11:105898408:GATC:G	donor_gain	1.0000
11:105898426:AGGT:A	donor_loss	1.0000

AlphaMissense

5922 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:105611085:G:C	G30R	1.000
11:105612276:G:A	G30D	1.000
11:105612279:G:A	G31D	1.000
11:105612416:T:C	F77L	1.000
11:105612417:T:G	F77C	1.000
11:105612418:T:A	F77L	1.000
11:105612418:T:G	F77L	1.000
11:105752983:T:A	C84S	1.000
11:105752983:T:C	C84R	1.000
11:105752984:G:A	C84Y	1.000
11:105752984:G:C	C84S	1.000
11:105752985:T:G	C84W	1.000
11:105753063:C:G	C110W	1.000
11:105903827:T:C	L300P	1.000
11:105903919:T:A	C331S	1.000
11:105903919:T:C	C331R	1.000
11:105903920:G:A	C331Y	1.000
11:105903920:G:C	C331S	1.000
11:105903921:T:G	C331W	1.000
11:105905250:A:C	R369S	1.000
11:105905250:A:T	R369S	1.000
11:105918718:C:T	P426S	1.000
11:105918719:C:A	P426Q	1.000
11:105918725:T:A	V428D	1.000
11:105918775:G:A	G445R	1.000
11:105918775:G:C	G445R	1.000
11:105918776:G:A	G445E	1.000
11:105918776:G:T	G445V	1.000
11:105918781:T:C	C447R	1.000
11:105918783:T:G	C447W	1.000

dbSNP variants (sampled 300 via entrez): RS1000036255 (11:105669195 C>G), RS1000037312 (11:105911644 G>C), RS1000039897 (11:105846405 G>T), RS1000041232 (11:105896418 CTTTAG>C), RS1000041875 (11:105710814 T>A,C), RS1000050410 (11:105772683 C>A), RS1000058007 (11:105629519 T>G), RS1000072765 (11:105629555 T>C), RS1000079974 (11:105867109 C>T), RS1000091131 (11:105889224 A>G), RS1000097138 (11:105935583 A>T), RS1000097711 (11:105688670 G>A), RS1000107929 (11:105943901 T>C), RS1000108130 (11:105629245 C>T), RS1000120057 (11:105758165 G>T)

Disease associations

OMIM: gene MIM:138246 | disease phenotypes: MIM:617864

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with or without seizures and gait abnormalities	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neurodevelopmental disorder with or without seizures and gait abnormalities	Moderate	AD

Mondo (4): neurodevelopmental disorder with or without seizures and gait abnormalities (MONDO:0060641), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), obesity disorder (MONDO:0011122)

Orphanet (4): Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000303	Mandibular prognathia
HP:0000322	Short philtrum
HP:0000400	Macrotia
HP:0000486	Strabismus
HP:0000609	Optic nerve hypoplasia
HP:0000639	Nystagmus
HP:0000736	Short attention span
HP:0000737	Irritability
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001319	Neonatal hypotonia
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0002072	Chorea
HP:0002079	Hypoplasia of the corpus callosum
HP:0002120	Cerebral cortical atrophy
HP:0002133	Status epilepticus
HP:0002267	Exaggerated startle response
HP:0002510	Spastic tetraplegia
HP:0002540	Inability to walk
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0010845	EEG with generalized slow activity
HP:0011800	Midface retrusion
HP:0011968	Feeding difficulties

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001858_15	Refractive error	6.000000e-09
GCST003262_503	Post bronchodilator FEV1	5.000000e-06
GCST003997_17	Myopia	1.000000e-11
GCST006291_112	Spherical equivalent or myopia (age of diagnosis)	5.000000e-17
GCST006631_10	Nicotine dependence and major depression (severity of comorbidity)	2.000000e-08
GCST007335_22	Age at first sexual intercourse	1.000000e-09
GCST010002_247	Refractive error	4.000000e-39
GCST90000047_171	Age at first sexual intercourse	2.000000e-10
GCST90020047_2	Glioma	5.000000e-19

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004847	age at onset
EFO:0007006	depressive symptom measurement
EFO:0009262	nicotine dependence symptom count
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2096670 (PROTEIN COMPLEX GROUP), CHEMBL3190 (SINGLE PROTEIN), 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: 952,182 (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
CHEMBL61593	CYCLOTHIAZIDE	4	4,410
CHEMBL575060	GLUTAMIC ACID	3	929,756
CHEMBL14935	TEZAMPANEL ANHYDROUS	2	106
CHEMBL39664	SELFOTEL	2	2,588
CHEMBL1277001	MIBAMPATOR	2	92
CHEMBL275040	KAINIC ACID	2	15,084
CHEMBL1276138	FARAMPATOR	2	146

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

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
LY392098	Positive	6.7	pEC50
LY404187	Positive	6.68	pEC50
cyclothiazide	Positive	5.41	pEC50

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

317 potent at pChembl≥5 of 383 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.57	Ki	2.7	nM	CHEMBL370038
8.44	Ki	3.6	nM	CHEMBL331696
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
8.10	Ki	7.9	nM	CHEMBL331644
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
7.70	Ki	19.9	nM	CHEMBL121553
7.66	Ki	22	nM	CHEMBL116565
7.66	Ki	22	nM	CHEMBL293613
7.65	EC50	22.6	nM	CHEMBL63355
7.64	IC50	23	nM	(R,S)-AMPA
7.52	IC50	30	nM	CHEMBL94859
7.48	EC50	32.8	nM	CHEMBL294506
7.40	Ki	40	nM	(R,S)-AMPA
7.40	Ki	40	nM	(S)-AMPA
7.40	IC50	40	nM	(R,S)-AMPA
7.35	Ki	44.4	nM	CHEMBL370941
7.34	EC50	45.8	nM	CHEMBL63355
7.31	Ki	49	nM	CHEMBL12989
7.28	EC50	53	nM	CHEMBL384847
7.28	IC50	52	nM	NBQX
7.27	Ki	54	nM	CHEMBL79348
7.25	EC50	56	nM	CHEMBL384847
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	EC50	68	nM	CHEMBL63417
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	EC50	77	nM	CHEMBL215090
7.11	Ki	78	nM	CHEMBL275334
7.10	EC50	80	nM	CHEMBL215575
7.10	IC50	80	nM	CHEMBL293206
7.09	EC50	82.1	nM	CHEMBL304375
7.08	Ki	84	nM	YM-90K

PubChem BioAssay actives

249 with measured affinity, of 489 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	239018: Binding affinity for ionotropic Glutamate receptor AMPA 4 expressed in Sf9 cells	ki	0.0027	uM
(2S)-2-amino-3-(6-chloro-3,5-dioxo-1,2,4-triazin-2-yl)propanoic acid	93111: Displacement of [3H]AMPA from human Ionotropic glutamate receptor AMPA 4 expressed in HEK293 cells	ki	0.0036	uM
(2S)-2-amino-3-(6-bromo-3,5-dioxo-1,2,4-triazin-2-yl)propanoic acid	93111: Displacement of [3H]AMPA from human Ionotropic glutamate receptor AMPA 4 expressed in HEK293 cells	ki	0.0079	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
(2S)-2-amino-3-(6-iodo-3,5-dioxo-1,2,4-triazin-2-yl)propanoic acid	93111: Displacement of [3H]AMPA from human Ionotropic glutamate receptor AMPA 4 expressed in HEK293 cells	ki	0.0199	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
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
N-[(1R,2R)-2-(4-iodophenyl)cyclopentyl]propane-2-sulfonamide	75673: Potentiation of responses mediated by 100 uM L-glutamate in transfected HEK293 cells expressing human homomeric iGluR4 flip receptors.	ec50	0.0226	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
N-[(1S,2R)-2-(4-iodophenyl)cyclopentyl]propane-2-sulfonamide	75673: Potentiation of responses mediated by 100 uM L-glutamate in transfected HEK293 cells expressing human homomeric iGluR4 flip receptors.	ec50	0.0328	uM
(2S)-2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid	239018: Binding affinity for ionotropic Glutamate receptor AMPA 4 expressed in Sf9 cells	ki	0.0400	uM
2-amino-3-[5-(2-ethyltetrazol-5-yl)-3-oxo-1,2-oxazol-4-yl]propanoic acid	239018: Binding affinity for ionotropic Glutamate receptor AMPA 4 expressed in Sf9 cells	ki	0.0444	uM
4-cyano-3-[4-(2-cyanophenyl)phenyl]-5-ethyl-1-methylpyrrole-2-carboxylic acid	270306: Activity at human recombinant iGluR4 flop expressed in HEK293 cells measured as change in intracellular calcium ion concentration in presence of glutamate by FLIPR assay	ec50	0.0530	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
N-[(1R,2R)-2-(4-bromophenyl)cyclopentyl]propane-2-sulfonamide	75673: Potentiation of responses mediated by 100 uM L-glutamate in transfected HEK293 cells expressing human homomeric iGluR4 flip receptors.	ec50	0.0680	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
4-cyano-5-ethyl-1-methyl-3-[4-(2-methylsulfanylphenyl)phenyl]pyrrole-2-carboxylic acid	270306: Activity at human recombinant iGluR4 flop expressed in HEK293 cells measured as change in intracellular calcium ion concentration in presence of glutamate by FLIPR assay	ec50	0.0770	uM
4-cyano-5-ethyl-3-[4-(2-fluorophenyl)phenyl]-1-methylpyrrole-2-carboxylic acid	270305: Activity at human recombinant iGluR4 flip expressed in HEK293 cells measured as change in intracellular calcium ion concentration in presence of glutamate by FLIPR assay	ec50	0.0800	uM
N-[(1S,2R)-2-(4-bromophenyl)cyclopentyl]propane-2-sulfonamide	75673: Potentiation of responses mediated by 100 uM L-glutamate in transfected HEK293 cells expressing human homomeric iGluR4 flip receptors.	ec50	0.0821	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
(2S)-2-amino-3-(6-methyl-3,5-dioxo-1,2,4-triazin-2-yl)propanoic acid	93111: Displacement of [3H]AMPA from human Ionotropic glutamate receptor AMPA 4 expressed in HEK293 cells	ki	0.0890	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
N-[(1R,2R)-2-(3,5-difluorophenyl)cyclopentyl]propane-2-sulfonamide	75673: Potentiation of responses mediated by 100 uM L-glutamate in transfected HEK293 cells expressing human homomeric iGluR4 flip receptors.	ec50	0.1180	uM
2-amino-3-(3-hydroxy-5-methyltriazol-4-yl)propanoic acid	2071188: Binding affinity to AMPA receptor (unknown origin)	ic50	0.1300	uM
N-[2-[4-(4-aminophenyl)phenyl]propyl]propane-2-sulfonamide	223222: Tested for potentiation towards human iGluR4 receptor expressed in HEK293 cells	ec50	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
4-cyano-3-[4-(2-ethoxyphenyl)phenyl]-5-ethyl-1-methylpyrrole-2-carboxylic acid	270306: Activity at human recombinant iGluR4 flop expressed in HEK293 cells measured as change in intracellular calcium ion concentration in presence of glutamate by FLIPR assay	ec50	0.1460	uM
N-[(2R)-2-[4-[4-[2-(methanesulfonamido)ethyl]phenyl]phenyl]propyl]propane-2-sulfonamide	536772: Inhibition of GluR4 expressed in HEK293 cells	ec50	0.1500	uM
3-[4-(2-chlorophenyl)phenyl]-4-cyano-5-ethyl-1-methylpyrrole-2-carboxylic acid	270306: Activity at human recombinant iGluR4 flop expressed in HEK293 cells measured as change in intracellular calcium ion concentration in presence of glutamate by FLIPR assay	ec50	0.1570	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
(2S)-2-amino-3-(4-oxo-1,2,5-thiadiazol-3-yl)propanoic acid	320602: Binding affinity at iGluR4o receptor expressed in sf9 cells by radioligand binding assay	ki	0.1820	uM
3-(4-tert-butylphenyl)-4-cyano-5-ethylthiophene-2-carboxylic acid	270081: Activity against human GLUR4 flip expressed in HEK293 cells assessed as glutamate-stimulated calcium influx by FLIPR assay	ec50	0.1830	uM
(2S)-2-amino-3-(3,5-dioxo-1,2,4-triazin-2-yl)propanoic acid	93111: Displacement of [3H]AMPA from human Ionotropic glutamate receptor AMPA 4 expressed in HEK293 cells	ki	0.1890	uM
N-[(1R,2R)-2-(4-nitrophenyl)cyclopentyl]propane-2-sulfonamide	75673: Potentiation of responses mediated by 100 uM L-glutamate in transfected HEK293 cells expressing human homomeric iGluR4 flip receptors.	ec50	0.1900	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)-2-amino-3-(5-nitro-2,4-dioxopyrimidin-1-yl)propanoic acid	93111: Displacement of [3H]AMPA from human Ionotropic glutamate receptor AMPA 4 expressed in HEK293 cells	ki	0.2070	uM
4-cyano-5-ethyl-1-methyl-3-(4-phenylphenyl)pyrrole-2-carboxylic acid	270305: Activity at human recombinant iGluR4 flip expressed in HEK293 cells measured as change in intracellular calcium ion concentration in presence of glutamate by FLIPR assay	ec50	0.2130	uM
3-(4-tert-butylphenyl)-4-cyano-5-methylsulfanylthiophene-2-carboxylic acid	270081: Activity against human GLUR4 flip expressed in HEK293 cells assessed as glutamate-stimulated calcium influx by FLIPR assay	ec50	0.2140	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	7
Benzo(a)pyrene	affects methylation, increases methylation	2
aristolochic acid I	decreases expression	1
bisphenol A	increases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Vorinostat	affects cotreatment, increases expression	1
Fonofos	increases methylation	1
Folic Acid	increases expression	1
Parathion	increases methylation	1
Sodium Fluoride	decreases expression	1
Testosterone	increases expression	1
Thalidomide	increases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	increases expression	1

ChEMBL screening assays

102 unique, capped per target: 83 binding, 19 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

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1SW	Abcam U-87MG GRIA4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder