SLC1A3

Summary

SLC1A3 (solute carrier family 1 member 3, HGNC:10941) is a protein-coding gene on chromosome 5p13.2, encoding Excitatory amino acid transporter 1 (P43003). Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate.

This gene encodes a member of a member of a high affinity glutamate transporter family. This gene functions in the termination of excitatory neurotransmission in central nervous system. Mutations are associated with episodic ataxia, Type 6. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6507 — RefSeq curated summary.

At a glance

• Gene–disease (curated): episodic ataxia type 6 (Definitive, ClinGen)
• GWAS associations: 14
• Clinical variants (ClinVar): 302 total
• Phenotypes (HPO): 86
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004172

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10941
Approved symbol	SLC1A3
Name	solute carrier family 1 member 3
Location	5p13.2
Locus type	gene with protein product
Status	Approved
Aliases	EAAT1, GLAST, EA6, GLAST1, GLAST-1
Ensembl gene	ENSG00000079215
Ensembl biotype	protein_coding
OMIM	600111
Entrez	6507

Gene structure

Transcript identifiers

Ensembl transcripts: 69 — 33 protein_coding, 14 protein_coding_CDS_not_defined, 11 retained_intron, 11 nonsense_mediated_decay

ENST00000265113, ENST00000381918, ENST00000416645, ENST00000502864, ENST00000504121, ENST00000505202, ENST00000505376, ENST00000506178, ENST00000506725, ENST00000509272, ENST00000512374, ENST00000513646, ENST00000513903, ENST00000514563, ENST00000612708, ENST00000613445, ENST00000624112, ENST00000679384, ENST00000679423, ENST00000679487, ENST00000679784, ENST00000679852, ENST00000679958, ENST00000679983, ENST00000679992, ENST00000680016, ENST00000680048, ENST00000680064, ENST00000680125, ENST00000680205, ENST00000680212, ENST00000680232, ENST00000680318, ENST00000680369, ENST00000680527, ENST00000680568, ENST00000680655, ENST00000680711, ENST00000680835, ENST00000680876, ENST00000680878, ENST00000680890, ENST00000680908, ENST00000681373, ENST00000681388, ENST00000681440, ENST00000681480, ENST00000681623, ENST00000681633, ENST00000681666, ENST00000681701, ENST00000681726, ENST00000681775, ENST00000681776, ENST00000681795, ENST00000681814, ENST00000681848, ENST00000681854, ENST00000681909, ENST00000681926, ENST00000858305, ENST00000858306, ENST00000858307, ENST00000858308, ENST00000936087, ENST00000936088, ENST00000936089, ENST00000963662, ENST00000963663

RefSeq mRNA: 5 — MANE Select: NM_004172 NM_001166695, NM_001166696, NM_001289939, NM_001289940, NM_004172

CCDS: CCDS3919, CCDS54844, CCDS78003, CCDS78004, CCDS93705

Canonical transcript exons

ENST00000265113 — 10 exons

Exon	Start	End
ENSE00000971213	36676892	36677184
ENSE00000971215	36679627	36679860
ENSE00000971216	36680395	36680589
ENSE00001889479	36686065	36688334
ENSE00003542142	36683864	36683998
ENSE00003559362	36674049	36674091
ENSE00003635627	36629450	36629587
ENSE00003680688	36671029	36671233
ENSE00003692876	36608329	36608604
ENSE00003844086	36606606	36606735

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 99.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 86.6810 / max 3629.3979, expressed in 1280 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56128	84.2319	1279
56145	0.3461	111
56133	0.2540	94
56132	0.2521	94
56134	0.2451	96
56135	0.2268	95
56143	0.1608	80
56150	0.1495	57
56148	0.1226	33
56130	0.1216	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.71	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.70	gold quality
medial globus pallidus	UBERON:0002477	99.55	gold quality
globus pallidus	UBERON:0001875	99.51	gold quality
lateral globus pallidus	UBERON:0002476	99.51	gold quality
CA1 field of hippocampus	UBERON:0003881	99.44	gold quality
inferior olivary complex	UBERON:0002127	99.35	gold quality
nucleus accumbens	UBERON:0001882	99.30	gold quality
middle temporal gyrus	UBERON:0002771	99.29	gold quality
cranial nerve II	UBERON:0000941	99.22	gold quality
amygdala	UBERON:0001876	99.22	gold quality
caudate nucleus	UBERON:0001873	99.20	gold quality
putamen	UBERON:0001874	99.20	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.20	gold quality
temporal lobe	UBERON:0001871	99.18	gold quality
entorhinal cortex	UBERON:0002728	99.10	gold quality
ganglionic eminence	UBERON:0004023	99.06	gold quality
corpus callosum	UBERON:0002336	99.05	gold quality
right frontal lobe	UBERON:0002810	98.92	gold quality
Ammon’s horn	UBERON:0001954	98.78	gold quality
superior vestibular nucleus	UBERON:0007227	98.77	gold quality
medulla oblongata	UBERON:0001896	98.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.76	gold quality
superior frontal gyrus	UBERON:0002661	98.65	gold quality
occipital lobe	UBERON:0002021	98.63	gold quality
paraflocculus	UBERON:0005351	98.56	gold quality
postcentral gyrus	UBERON:0002581	98.55	gold quality
parietal lobe	UBERON:0001872	98.54	gold quality
primary visual cortex	UBERON:0002436	98.54	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.52	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	4925.72
E-HCAD-30	yes	4439.79
E-HCAD-25	yes	3426.98
E-GEOD-93593	yes	3163.77
E-GEOD-180759	yes	2941.73
E-HCAD-56	yes	2312.58
E-GEOD-137537	yes	1486.72
E-GEOD-75140	yes	1429.89
E-HCAD-36	yes	994.86
E-MTAB-8894	yes	471.14
E-MTAB-7052	yes	424.18
E-HCAD-5	yes	56.30
E-MTAB-7316	yes	36.04
E-ANND-3	yes	20.89
E-GEOD-84465	yes	14.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREB1, JUN, LRRFIP1, NFKB, PPARG, SP1, SP3, TFAP2A, USF1, YY1

miRNA regulators (miRDB)

123 targeting SLC1A3, 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-1193	100.00	65.93	529
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-548AZ-3P	99.82	70.56	3549

Literature-anchored findings (GeneRIF, showing 40)

• Dose-dependent modulation of EAAT1-mediated aspartate transport by benzodiazepines suggests a role of glial as well as neuronal transporters in drug action. (PMID:11792462)
• EAAT1 was strongly expressed in a subset of cortical pyramidal neurons in dementia cases showing Alzheimer-type pathology. In addition, tau (which is a marker of neurofibrillary pathology) colocalized to those same pyramidal cells that expressed EAAT1 (PMID:11826152)
• Data show that excitatory amino acid transporter (EAAT)-1 was expressed by activated macrophages/microglia in all HIV-infected cases but not in HIV-negative controls. (PMID:12769187)
• To test whether Nedd4-2, SGK1, SGK3 and protein kinase B regulate EAAT1, cRNA encoding EAAT1 was injected into Xenopus oocytes with or without injection of Nedd4-2, constitutively active[CA] S422DSGK1, inactive K127NSGK1, SGK3 and/or CA T308D,S473DPKB (PMID:12911626)
• Transcriptional regulation of human excitatory amino acid transporter 1 (EAAT1): cloning of the EAAT1 promoter and characterization of its basal and inducible activity in human astrocytes. (PMID:14713304)
• We observed decreased glutamate uptake V(max), without modification of transporter affinity, in aging, which could be linked to the selective decrease of EAAT1 expression and mRNA. Moreover, in AD patients we found a further EAAT1 reduction. (PMID:14749132)
• data show specific localization of glutamate transporters EAAT1, EAAT2 and EAAT3 in the human placenta during development (PMID:15135231)
• Only activated macrophages/microglia (AMM) expressed EAAT-1. Proportion of AMM expressing EAAT-1 did not correlate with severity of neuronal apoptosis, spongiosis, astrocytosis, microgliosis, or PrP deposition, but only with disease duration. (PMID:15535133)
• EAAT1 parameters were mutually correlated (p<0.01) and correlations were shown with dementia severity (p<0.05 MMSE-expression, p<0.005 MMSE-mRNA). (PMID:15718040)
• Genetic variation in SLC1A3 may contribute to susceptibility to ADHD. (PMID:15950021)
• EAAT1ex9skip splice variant is a negative regulator of full-length EAAT1 function in the human brain (PMID:16042756)
• enhanced expression of glutamate transporters in multiple sclerosis constitutes a regulatory response of glial cells to toxic levels of glutamate in the CNS during inflammation and neurodegeneration (PMID:16061389)
• Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia. (PMID:16116111)
• the activity of glutamate transporter GLAST/EAAT1 can effectively regulate the cell surface expression of glutamine/neutral amino acid transporter ASCT2 in human fetal astrocytes (PMID:16516348)
• Rearrangements in the tertiary structure of the EAAT1 translocation pore during transport provide constraints for modeling the structural dynamics associated with transport. (PMID:16877378)
• SLC1A3 is unlikely to be a major susceptibility gene for schizophrenia in the Japanese population. (PMID:17221839)
• Activity of GLAST directs FXYD2 protein/gamma subunit to the cell surface, that leads to the activation of the astroglial sodium pump. (PMID:17316900)
• Continued expression of GLAST by neural progenitor cells in the transgenic mouse brain raises the possibility that GLAST may have an unanticipated role in regulating their behavior. (PMID:17581948)
• We documented for the first time the expression of the mGluR5 and EAAT1 in MG-63 cells, as well as the ability of dexamethasone to upregulate the expression of the mGluR5 and EAAT1 in the MG-63 cells. (PMID:17627080)
• Mutations in transmembrane domains 5 and 7 of the human excitatory amino acid transporter 1 affect the substrate-activated anion channel (PMID:17676873)
• No pathogenic mutation were identified in SLC1A3. (PMID:18446307)
• increased expression in the prefrontal cortex of chronic alcoholics (PMID:18657127)
• analysis of the importance of Leu-303 or its counterpart Leu-391 in human EAAT1 (hEAAT1) (PMID:18678877)
• We broadened the clinical spectrum associated with SLC1A3 mutations to include milder manifestations of EA without seizures or alternating hemiplegia. The severity of EA6 symptoms is related to the extent of glutamate transporter dysfunction. (PMID:19139306)
• immunoreactivity for EAAT-1, but not EAAT-2, distinguishes neoplastic choroid plexus (CP) from non-neoplastic CP and might be of help in making a diagnosis especially in well differentiated CP tissue (PMID:19283393)
• The expression of EAAT-1 and EAAT-2 was reduced to approximately 40% and 25%, respectively, in CA1 of the hippocampus in intractable temporal lobe epilepsy. (PMID:19338517)
• These results indicate that E219D is a functional SLC1A3 variant that is presented in a small number of individuals with Tourette syndrome. (PMID:21233784)
• There is no association between SLC1A3 and normal tension glaucoma (NTG), suggesting that the SLC1A3 gene may not be an associated factor in NTG pathogenesis. (PMID:21528001)
• SLC2A1/GLUT1, SLC1A3/EAAT1, and SLC1A2/EAAT2 were the main SLC proteins whereas ABCG2/BCRP, ABCB1/MDR1, ABCA2 and ABCA8 were the main ABC quantified in isolated brain microvessels (PMID:21707071)
• findings suggest that allelic variability in SLC1A2/3, 5-HTR1B and NTRK2 may be relevant to the underlying diathesis for suicidal acts. (PMID:21711518)
• water and urea permeation properties of wild-type EAAT1 and two mutant transporters were measured to identify which permeation pathway facilitates the movement of these molecules (PMID:21732909)
• A series of single cysteine substitutions in the helical hairpin HP2 of excitatory amino acid transporter 1 form intersubunit disulfide cross-links within the trimer. (PMID:21876140)
• Close functional similarities of the GLAST/EAAT-1 promoter regions in man and rat exist which point to a species-specific function of the GLAST/EAAT-1 3’-UTR in constitutive and regulated GLAST/EAAT-1 expression. (PMID:22252783)
• The accessibility in the external part of the TM5 of the glutamate transporter EAAT1 is conformationally sensitive during the transport cycle. (PMID:22292083)
• Increased SLC1A3 expression in the cerebellum of elderly schizophrenia patients indicates facilitated transport and may result in reduced glutamate neurotransmission. (PMID:22424243)
• Letter: report expression of dishevelled-3 and EAAT1 and glutamine metabolism in malignant pleural mesothelioma. (PMID:22569537)
• EAAT-1 expression was found in 91% of choroid plexus tumors and was absent in endolymphatic sac tumors. (PMID:22706862)
• Episodic ataxia type 6 represents the first human disease found to be associated with altered function of excitatory amino acid transporter anion channels. (PMID:23107647)
• Decreased expression of EAAT1 protein remodels glutamate neurotransmission in the superior temporal gyrus in schizophrenia. (PMID:23356950)
• Major depressive disorder is associated with unhealthy astrocytes in the noradrenergic Locus Coeruleus, characterized here by a reduction in astrocyte glutamate transporter expression. (PMID:23415275)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc1a3b	ENSDARG00000043148
danio_rerio	slc1a3a	ENSDARG00000104431
mus_musculus	Slc1a3	ENSMUSG00000005360
rattus_norvegicus	Slc1a3	ENSRNOG00000016163

Paralogs (6): SLC1A6 (ENSG00000105143), SLC1A5 (ENSG00000105281), SLC1A1 (ENSG00000106688), SLC1A2 (ENSG00000110436), SLC1A4 (ENSG00000115902), SLC1A7 (ENSG00000162383)

Protein

Protein identifiers

Excitatory amino acid transporter 1 — P43003 (reviewed: P43003)

Alternative names: Sodium-dependent glutamate/aspartate transporter 1, Solute carrier family 1 member 3

All UniProt accessions (25): P43003, A0A087WT87, A0A087X0U3, A0A7P0T7Q9, A0A7P0T800, A0A7P0T807, A0A7P0T8H5, A0A7P0T8P5, A0A7P0T8Q1, A0A7P0T8R2, A0A7P0T8T4, A0A7P0T911, A0A7P0T9A4, A0A7P0T9P1, A0A7P0T9Z4, A0A7P0TA03, A0A7P0TAF5, A0A7P0TAG7, A0A7P0TAW2, A0A7P0TB50, A0A7P0Z4F7, A0A7P0Z4R4, E7EUS7, E7EUV6, Q7Z5T0

UniProt curated annotations — full annotation on UniProt →

Function. Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate. Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion. Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport. Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate.

Subunit / interactions. Homotrimer.

Subcellular location. Cell membrane.

Tissue specificity. Detected in brain. Detected at very much lower levels in heart, lung, placenta and skeletal muscle. Highly expressed in cerebellum, but also found in frontal cortex, hippocampus and basal ganglia.

Post-translational modifications. Glycosylated.

Disease relevance. Episodic ataxia 6 (EA6) [MIM:612656] A disorder characterized by episodic ataxia, seizures, migraine and alternating hemiplegia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains eight transmembrane regions plus two helical hairpins that dip into the membrane. These helical hairpin structures play an important role in the transport process. The first enters the membrane from the cytoplasmic side, the second one from the extracellular side. During the transport cycle, the regions involved in amino acid transport, and especially the helical hairpins, move vertically by about 15-18 Angstroms, alternating between exposure to the aqueous phase and reinsertion in the lipid bilayer. In contrast, the regions involved in trimerization do not move.

Miscellaneous. Expressed throughout the CNS, both in gray matter and axonal tracts, at levels ranging between 10% and 20% of isoform 1. Localizes to ER, has no functional glutamate uptake activity, and exerts a dominant negative effect isoform 1.

Similarity. Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A3 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P43003-1	1	yes
P43003-2	2, EAAT1ex9skip

RefSeq proteins (5): NP_001160167, NP_001160168, NP_001276868, NP_001276869, NP_004163* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001991	Na-dicarboxylate_symporter	Family
IPR018107	Na-dicarboxylate_symporter_CS	Conserved_site
IPR036458	Na:dicarbo_symporter_sf	Homologous_superfamily
IPR050746	DAACS	Family

Pfam: PF00375

Catalyzed reactions (Rhea), 3 shown:

• K(+)(in) + L-glutamate(out) + 3 Na(+)(out) + H(+)(out) = K(+)(out) + L-glutamate(in) + 3 Na(+)(in) + H(+)(in) (RHEA:70699)
• K(+)(in) + L-aspartate(out) + 3 Na(+)(out) + H(+)(out) = K(+)(out) + L-aspartate(in) + 3 Na(+)(in) + H(+)(in) (RHEA:70851)
• D-aspartate(out) + K(+)(in) + 3 Na(+)(out) + H(+)(out) = D-aspartate(in) + K(+)(out) + 3 Na(+)(in) + H(+)(in) (RHEA:71379)

UniProt features (68 total): helix 26, topological domain 11, binding site 10, transmembrane region 8, mutagenesis site 3, intramembrane region 2, sequence variant 2, turn 2, chain 1, modified residue 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5LM4	X-RAY DIFFRACTION	3.1
5LLM	X-RAY DIFFRACTION	3.25
7AWM	X-RAY DIFFRACTION	3.25
5LLU	X-RAY DIFFRACTION	3.32
7AWQ	X-RAY DIFFRACTION	3.65
5MJU	X-RAY DIFFRACTION	3.71
7AWP	X-RAY DIFFRACTION	3.91
7AWN	X-RAY DIFFRACTION	3.92
7NPW	ELECTRON MICROSCOPY	3.99

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43003-F1	81.92	0.49

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 (10): 363–365; 394; 396; 398; 402; 443–447; 476; 483; 483; 487

Post-translational modifications (1): 512

Mutagenesis-validated functional residues (3):

Position	Phenotype
363	loss of electrogenic glutamate transport. strongly decreased l-aspartate and l-glutamate uptake combined with strongly i
477	strongly decreased l-aspartate and l-glutamate uptake combined with strongly increased permeability ot other ions; when
523	no effect on activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-210455	Astrocytic Glutamate-Glutamine Uptake And Metabolism
R-HSA-210500	Glutamate Neurotransmitter Release Cycle
R-HSA-5619062	Defective SLC1A3 causes episodic ataxia 6 (EA6)
R-HSA-9958863	SLC-mediated transport of amino acids
R-HSA-425393

MSigDB gene sets: 511 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MODULE_274, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_COCAINE, GOBP_NEUROTRANSMITTER_UPTAKE, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, TTTGTAG_MIR520D, MODULE_563, GOCC_CELL_SURFACE, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_NEUROGENESIS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS

GO Biological Process (32): neurotransmitter uptake (GO:0001504), monoatomic ion transport (GO:0006811), neurotransmitter transport (GO:0006836), intracellular sodium ion homeostasis (GO:0006883), chemical synaptic transmission (GO:0007268), sensory perception of sound (GO:0007605), response to xenobiotic stimulus (GO:0009410), response to light stimulus (GO:0009416), GABA biosynthetic process (GO:0009449), response to wounding (GO:0009611), L-glutamate transmembrane transport (GO:0015813), cranial nerve development (GO:0021545), auditory behavior (GO:0031223), response to antibiotic (GO:0046677), cell morphogenesis involved in neuron differentiation (GO:0048667), positive regulation of synaptic transmission (GO:0050806), neuromuscular process controlling balance (GO:0050885), L-glutamate import (GO:0051938), transepithelial transport (GO:0070633), D-aspartate import across plasma membrane (GO:0070779), cellular response to cocaine (GO:0071314), potassium ion transmembrane transport (GO:0071805), L-glutamate import across plasma membrane (GO:0098712), L-aspartate import across plasma membrane (GO:0140009), transport across blood-brain barrier (GO:0150104), chloride transmembrane transport (GO:1902476), amino acid transport (GO:0006865), neutral amino acid transport (GO:0015804), transmembrane transport (GO:0055085), import into cell (GO:0098657), L-alpha-amino acid transmembrane transport (GO:1902475), carboxylic acid transmembrane transport (GO:1905039)

GO Molecular Function (11): L-glutamate transmembrane transporter activity (GO:0005313), high-affinity L-glutamate transmembrane transporter activity (GO:0005314), neutral L-amino acid transmembrane transporter activity (GO:0015175), glutamate:sodium symporter activity (GO:0015501), glutamate binding (GO:0016595), metal ion binding (GO:0046872), protein binding (GO:0005515), acidic amino acid transmembrane transporter activity (GO:0015172), L-amino acid transmembrane transporter activity (GO:0015179), symporter activity (GO:0015293), amino acid binding (GO:0016597)

GO Cellular Component (12): plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), cell surface (GO:0009986), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), neuron projection (GO:0043005), neuronal cell body (GO:0043025), synapse (GO:0045202), perinuclear region of cytoplasm (GO:0048471), membrane protein complex (GO:0098796), cell projection (GO:0042995), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Neurotransmitter uptake and metabolism In glial cells	1
Neurotransmitter release cycle	1
SLC transporter disorders	1
SLC-mediated transmembrane transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
transport	3
amino acid transmembrane transporter activity	3
response to chemical	2
L-alpha-amino acid transmembrane transport	2
acidic amino acid transport	2
binding	2
membrane	2
cytoplasm	2
neurotransmitter transport	1
import into cell	1
intracellular monoatomic cation homeostasis	1
sodium ion homeostasis	1
anterograde trans-synaptic signaling	1
sensory perception of mechanical stimulus	1
response to radiation	1
amino acid biosynthetic process	1
non-proteinogenic amino acid biosynthetic process	1
response to stress	1
L-glutamate import	1
nerve development	1
mechanosensory behavior	1
response to auditory stimulus	1
cell morphogenesis	1
neuron differentiation	1
neuron development	1
chemical synaptic transmission	1
positive regulation of cell communication	1
positive regulation of signaling	1
modulation of chemical synaptic transmission	1
musculoskeletal movement	1
neuromuscular process	1
dicarboxylic acid transport	1
L-amino acid transport	1
D-aspartate transmembrane transport	1
amino acid import across plasma membrane	1
dicarboxylic acid transmembrane transporter activity	1
acidic amino acid transmembrane transporter activity	1
L-amino acid transmembrane transporter activity	1
L-glutamate transmembrane transport	1

Protein interactions and networks

STRING

2700 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC1A3	GLUL	P15104	812
SLC1A3	GFAP	P14136	763
SLC1A3	SLC38A3	Q99624	754
SLC1A3	NFIA	Q12857	752
SLC1A3	ALDH1L1	O75891	751
SLC1A3	CACNB4	O00305	748
SLC1A3	GRIN2B	Q13224	738
SLC1A3	NES	P48681	736
SLC1A3	NFIB	O00712	721
SLC1A3	FABP7	O15540	715
SLC1A3	WDR70	Q9NW82	697
SLC1A3	S100B	P04271	697
SLC1A3	NUP155	O75694	668
SLC1A3	KCNJ10	P78508	664
SLC1A3	CPLANE1	Q9H799	657

IntAct

208 interactions, top by confidence:

A	B	Type	Score
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
SLC1A3	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.590
PDZK1	SLC1A3	psi-mi:“MI:0407”(direct interaction)	0.590
TMEM120B	SLC1A3	psi-mi:“MI:0915”(physical association)	0.560
SLC1A3	TMEM128	psi-mi:“MI:0915”(physical association)	0.560
MGST3	SLC1A3	psi-mi:“MI:0915”(physical association)	0.560
SLC1A3	BTN2A2	psi-mi:“MI:0915”(physical association)	0.560
KCTD17	CBX4	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
SLC1A3	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
SNX27	SLC1A3	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	APBA3	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	LIN7B	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
MPDZ	SLC1A3	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	PTPN13	psi-mi:“MI:0407”(direct interaction)	0.440
SLC1A3	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (293): SLC1A3 (Two-hybrid), SLC1A3 (Affinity Capture-MS), SLC1A3 (Proximity Label-MS), SLC1A3 (Proximity Label-MS), SLC1A3 (Affinity Capture-MS), SLC1A3 (Affinity Capture-MS), SLC1A3 (Affinity Capture-MS), SLC1A3 (Proximity Label-MS), SLC1A3 (Proximity Label-MS), SLC1A3 (Proximity Label-MS), SLC1A3 (Proximity Label-MS), SLC1A3 (Proximity Label-MS), SLC1A3 (Synthetic Lethality), BTN2A2 (Two-hybrid), TMEM128 (Two-hybrid)

ESM2 similar proteins: A0A2K2BF92, A0A6P3HVI0, A1L3P4, A2VDL4, A4IHB9, B9H7I1, D3ZJ25, D4A7H1, E7EXX2, F7B113, O00341, O35874, O54902, O57321, P24942, P31596, P31597, P43003, P43004, P43005, P43006, P46411, P48763, P49281, P49282, P50482, P51906, P51907, P51912, P56564, Q0D7E4, Q3ZAS0, Q4R7S2, Q4ZJI4, Q5BKR2, Q5M7K3, Q5R6B8, Q6DFC0, Q86UD5, Q8BLV3

Diamond homologs: A2RGC2, A2VDL4, D3ZJ25, O00341, O19105, O35544, O35874, O35921, O57321, O59010, P0DF78, P0DF79, P24942, P31596, P31597, P43003, P43004, P43005, P43006, P43007, P46411, P48664, P51906, P51907, P51912, P56564, Q10901, Q15758, Q1J8E1, Q1JDG4, Q1JII6, Q1JND7, Q21353, Q21751, Q22682, Q25605, Q48V75, Q4R8W8, Q5XDS5, Q8JZR4

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
2-Amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7-(naphthalen-1-YL)-5-oxo-4H-chromene-3-carbonitrile	“down-regulates activity”	SLC1A3	“chemical inhibition”
SLC1A3	“up-regulates quantity”	“glutamic acid”	relocalization
CAV1	“down-regulates activity”	SLC1A3	binding
SGK1	“up-regulates activity”	SLC1A3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 164 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	8	41.5×	3e-09
Unblocking of NMDA receptors, glutamate binding and activation	5	24.7×	1e-04
Negative regulation of NMDA receptor-mediated neuronal transmission	5	24.7×	1e-04
Assembly and cell surface presentation of NMDA receptors	10	23.1×	3e-09
Dopamine Neurotransmitter Release Cycle	5	22.6×	1e-04
Long-term potentiation	5	21.6×	2e-04
Neurexins and neuroligins	10	17.9×	3e-08
Protein-protein interactions at synapses	6	14.5×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	34.0×	3e-09
receptor clustering	7	28.4×	2e-06
protein localization to synapse	5	24.9×	2e-04
regulation of postsynaptic membrane neurotransmitter receptor levels	6	19.3×	1e-04
Ras protein signal transduction	6	8.0×	6e-03
establishment of localization in cell	7	7.3×	3e-03
protein-containing complex assembly	9	6.7×	8e-04
cell-cell adhesion	10	6.6×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	166
Likely benign	56
Benign	39

Top pathogenic / likely-pathogenic (0)

SpliceAI

2614 predictions. Top by Δscore:

Variant	Effect	Δscore
5:36607207:ACT:A	acceptor_gain	1.0000
5:36608327:A:AG	acceptor_gain	1.0000
5:36608328:G:GG	acceptor_gain	1.0000
5:36608328:GTT:G	acceptor_gain	1.0000
5:36608328:GTTGT:G	acceptor_gain	1.0000
5:36608603:GG:G	donor_gain	1.0000
5:36608604:GG:G	donor_gain	1.0000
5:36629445:TTCA:T	acceptor_loss	1.0000
5:36629446:TCA:T	acceptor_loss	1.0000
5:36629447:CA:C	acceptor_loss	1.0000
5:36629448:A:AC	acceptor_loss	1.0000
5:36629448:A:AG	acceptor_gain	1.0000
5:36629448:AG:A	acceptor_gain	1.0000
5:36629449:G:GT	acceptor_gain	1.0000
5:36629449:GG:G	acceptor_gain	1.0000
5:36629449:GGT:G	acceptor_gain	1.0000
5:36629449:GGTA:G	acceptor_gain	1.0000
5:36629449:GGTAC:G	acceptor_gain	1.0000
5:36629538:G:GT	donor_gain	1.0000
5:36629585:CAGG:C	donor_loss	1.0000
5:36629586:AG:A	donor_loss	1.0000
5:36629587:GG:G	donor_loss	1.0000
5:36629588:GT:G	donor_loss	1.0000
5:36629589:T:G	donor_loss	1.0000
5:36676889:A:AG	acceptor_gain	1.0000
5:36676890:A:G	acceptor_gain	1.0000
5:36676891:G:GA	acceptor_gain	1.0000
5:36676891:GTTT:G	acceptor_gain	1.0000
5:36676891:GTTTA:G	acceptor_gain	1.0000
5:36677182:GTG:G	donor_gain	1.0000

AlphaMissense

3554 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:36608604:G:C	G61R	1.000
5:36629462:G:A	G65E	1.000
5:36629521:G:T	G85W	1.000
5:36629561:C:G	P98R	1.000
5:36629564:T:A	L99H	1.000
5:36629564:T:C	L99P	1.000
5:36629575:A:C	S103R	1.000
5:36629577:T:A	S103R	1.000
5:36629577:T:G	S103R	1.000
5:36671110:C:A	A134D	1.000
5:36671121:G:C	G138R	1.000
5:36671122:G:A	G138D	1.000
5:36679640:G:C	G292R	1.000
5:36679641:G:A	G292D	1.000
5:36679653:T:C	L296P	1.000
5:36679707:T:C	L314P	1.000
5:36679736:G:C	G324R	1.000
5:36679842:C:A	A359D	1.000
5:36680400:C:A	A367D	1.000
5:36680406:T:C	L369P	1.000
5:36680480:G:A	G394R	1.000
5:36680480:G:C	G394R	1.000
5:36680481:G:A	G394E	1.000
5:36680494:C:A	N398K	1.000
5:36680494:C:G	N398K	1.000
5:36680496:T:C	M399T	1.000
5:36680497:G:A	M399I	1.000
5:36680497:G:C	M399I	1.000
5:36680497:G:T	M399I	1.000
5:36680498:G:C	D400H	1.000

dbSNP variants (sampled 300 via entrez): RS1000000092 (5:36685624 A>C), RS1000057334 (5:36660746 A>T), RS1000086265 (5:36672047 G>A,T), RS1000136679 (5:36611427 GAC>G), RS1000177439 (5:36648514 T>C), RS1000191037 (5:36623048 G>A,T), RS1000222637 (5:36606278 T>A,C), RS1000276678 (5:36655062 G>A), RS1000313529 (5:36646888 C>T), RS1000366362 (5:36660441 T>G), RS1000371907 (5:36640462 G>A), RS1000425075 (5:36611090 T>C), RS1000440980 (5:36661104 C>T), RS1000486533 (5:36640795 C>A,G,T), RS1000505277 (5:36679208 A>G,T)

Disease associations

OMIM: gene MIM:600111 | disease phenotypes: MIM:612656

GenCC curated gene-disease

Disease	Classification	Inheritance
episodic ataxia type 6	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
episodic ataxia type 6	Definitive	AD

Mondo (2): episodic ataxia type 6 (MONDO:0012982), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042)

Orphanet (2): Episodic ataxia type 6 (Orphanet:209967), Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341)

HPO phenotypes

86 total (30 of 86 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000297	Facial hypotonia
HP:0000348	High forehead
HP:0000565	Esotropia
HP:0000571	Hypometric saccades
HP:0000577	Exotropia
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000651	Diplopia
HP:0000657	Oculomotor apraxia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0000975	Hyperhidrosis
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001266	Choreoathetosis
HP:0001269	Hemiparesis
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001321	Cerebellar hypoplasia
HP:0001332	Dystonia
HP:0001337	Tremor

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST005580_269	Intraocular pressure	5.000000e-10
GCST005580_298	Intraocular pressure	3.000000e-09
GCST006288_213	Heel bone mineral density	6.000000e-09
GCST006288_318	Heel bone mineral density	2.000000e-07
GCST006288_532	Heel bone mineral density	1.000000e-13
GCST006427_36	Depression in smokers	5.000000e-06
GCST006979_764	Heel bone mineral density	2.000000e-22
GCST007014_4	Lumbar spine bone mineral density (trabecular)	2.000000e-08
GCST007015_13	Lumbar spine bone mineral density (integral)	3.000000e-07
GCST010725_6	Malaria	9.000000e-07
GCST010725_66	Malaria	1.000000e-06
GCST010725_85	Malaria	5.000000e-06
GCST90011900_101	Serum alkaline phosphatase levels	9.000000e-15
GCST90013406_9	Liver enzyme levels (alkaline phosphatase)	1.000000e-43

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0009270	heel bone mineral density
EFO:0007620	volumetric bone mineral density
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567207	Episodic Ataxia, Type 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3085 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,662,934 (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
CHEMBL274323	ASPARTIC ACID	3	733,178
CHEMBL575060	GLUTAMIC ACID	3	929,756

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1529461	SLC1A3		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Glutamate transporter subfamily

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

Ligand	Action	Affinity	Parameter
[3H]ETB-TBOA	Binding	7.8	pKd
UCPH-101	Inhibition	6.9	pIC50
DL-TBOA	Inhibition	5.0	pKB

Binding affinities (BindingDB)

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

Ligand	Measure	Value
WAY-213394	KI	1970 nM
WAY-212922	KI	3430 nM
N-[4-(2-BROMO-4,5-DIFLUOROPHENOXY)PHENYL]-L-ASPARAGINE	KI	5000 nM

ChEMBL bioactivities

192 potent at pChembl≥5 of 292 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	EC50	0.02	nM	CHEMBL5571220
9.22	EC50	0.6	nM	CHEMBL5563875
8.90	IC50	1.259	nM	CHEMBL4176427
8.80	EC50	1.6	nM	CHEMBL5593916
8.74	IC50	1.8	nM	CHEMBL5572574
8.70	EC50	2	nM	CHEMBL5564905
8.65	EC50	2.24	nM	CHEMBL5571181
8.56	EC50	2.75	nM	CHEMBL5594077
8.45	IC50	3.548	nM	CHEMBL1257519
8.44	IC50	3.6	nM	CHEMBL1257519
8.40	EC50	4	nM	CHEMBL5590998
8.38	IC50	4.2	nM	CHEMBL5572226
8.29	IC50	5.1	nM	CHEMBL4176427
8.28	EC50	5.3	nM	CHEMBL5573416
8.21	IC50	6.1	nM	CHEMBL4173045
8.21	IC50	6.166	nM	CHEMBL4173045
7.97	IC50	10.72	nM	CHEMBL4176482
7.96	IC50	11	nM	CHEMBL4176482
7.93	IC50	11.75	nM	CHEMBL4177507
7.92	IC50	12	nM	CHEMBL4177507
7.68	IC50	21	nM	CHEMBL4165811
7.68	IC50	20.89	nM	CHEMBL4165811
7.66	IC50	22	nM	CHEMBL1257519
7.51	IC50	31	nM	CHEMBL4162363
7.51	IC50	30.9	nM	CHEMBL4162363
7.24	EC50	58	nM	CHEMBL5583680
7.00	IC50	100	nM	CHEMBL2113115
7.00	IC50	100	nM	CHEMBL2113122
6.94	IC50	116	nM	CHEMBL5423219
6.92	IC50	120	nM	CHEMBL474133
6.91	IC50	123	nM	CHEMBL474133
6.89	IC50	130	nM	CHEMBL2113112
6.88	EC50	132	nM	CHEMBL1393473
6.82	IC50	150	nM	CHEMBL2113116
6.70	IC50	200	nM	CHEMBL2113111
6.70	IC50	200	nM	CHEMBL2113118
6.70	IC50	200	nM	CHEMBL1257519
6.52	IC50	300	nM	CHEMBL424838
6.52	IC50	300	nM	CHEMBL2113117
6.52	IC50	300	nM	CHEMBL1628570
6.50	IC50	316.2	nM	CHEMBL3960774
6.50	IC50	320	nM	CHEMBL3960774
6.47	IC50	338.8	nM	CHEMBL1259233
6.46	IC50	350	nM	CHEMBL3975687
6.46	IC50	344	nM	CHEMBL5573743
6.44	IC50	363.1	nM	CHEMBL3975687
6.43	IC50	370	nM	CHEMBL4790691
6.43	IC50	371.5	nM	CHEMBL4790691
6.42	IC50	380.2	nM	CHEMBL3974720
6.42	IC50	380	nM	CHEMBL3974720

PubChem BioAssay actives

192 with measured affinity, of 606 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
1-[(1-benzyltetrazol-5-yl)-pyridin-3-ylmethyl]-4-methylpiperazine	2105513: Positive allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ec50	<0.0001	uM
1-cyclohexyl-4-[[1-(2-phenylethyl)tetrazol-5-yl]-pyridin-3-ylmethyl]piperazine	2105513: Positive allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ec50	0.0006	uM
(2S,3S)-2-amino-3-[[3-[3-[4-(trifluoromethyl)phenyl]propanoylamino]phenyl]methoxy]butanedioic acid	1356069: Inhibition of human EAAT1 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0013	uM
4-[(1-benzyltetrazol-5-yl)-(4-methylpiperazin-1-yl)methyl]benzonitrile	2105513: Positive allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ec50	0.0016	uM
1-[(1-benzyltetrazol-5-yl)-pyridin-2-ylmethyl]-4-methylpiperazine	2105511: Negative allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ic50	0.0018	uM
5-[(4-methylpiperazin-1-yl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-1H-pyridin-2-one	2105513: Positive allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ec50	0.0020	uM
1-[(1-benzyltetrazol-5-yl)-pyridin-4-ylmethyl]-4-methylpiperazine	2105513: Positive allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ec50	0.0022	uM
1-[(6-fluoro-3-pyridinyl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-4-methylpiperazine	2105513: Positive allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ec50	0.0027	uM
(2S,3S)-2-amino-3-[[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]butanedioic acid	1356069: Inhibition of human EAAT1 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0035	uM
4-[(4-methylpiperazin-1-yl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]benzonitrile	2105513: Positive allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ec50	0.0040	uM
1-[(1-benzyltetrazol-5-yl)-(4-chlorophenyl)methyl]-4-methylpiperazine	2105511: Negative allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ic50	0.0042	uM
N-benzyl-2-(4-cyanophenyl)-2-(4-methylpiperazin-1-yl)acetamide	2105513: Positive allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ec50	0.0053	uM
(2S,3S)-2-amino-3-[[3-[[3-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]butanedioic acid	1356069: Inhibition of human EAAT1 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0061	uM
(2S,3S)-2-amino-4-[4-(2-bromo-4,5-difluorophenoxy)anilino]-4-oxo-3-phenylmethoxybutanoic acid	1356069: Inhibition of human EAAT1 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0107	uM
(2S,3S)-2-amino-4-(9H-fluoren-2-ylamino)-4-oxo-3-phenylmethoxybutanoic acid	1356069: Inhibition of human EAAT1 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0118	uM
(2S,3S)-2-amino-3-[[3-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]phenyl]methoxy]butanedioic acid	1356069: Inhibition of human EAAT1 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0209	uM
(2S,3S)-2-amino-3-[[3-[[2-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]butanedioic acid	1356069: Inhibition of human EAAT1 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0309	uM
N-[2-(4-fluorophenyl)ethyl]-2-(4-methylpiperazin-1-yl)-2-pyridin-3-ylacetamide	2105513: Positive allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ec50	0.0580	uM
(2S)-2-amino-4-oxo-4-[4-[3-(trifluoromethyl)phenyl]anilino]butanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.1000	uM
(2S)-2-amino-4-[(7-fluoro-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.1000	uM
(2S,3S)-2-amino-3-[[3-[(4-methoxybenzoyl)amino]phenyl]methoxy]butanedioic acid	2028656: Inhibition of human EAAT1 transfected in African green monkey COS-1 cells assessed as reduction in [14C]glutamate uptake	ic50	0.1160	uM
2-amino-4-(4-methoxyphenyl)-7-naphthalen-1-yl-5-oxo-4,6,7,8-tetrahydrochromene-3-carbonitrile	348019: Activity at human EAAT1 expressed in HEK293 cells assessed as inhibition of Glu-induced fluorescent response by FLIPR membrane potential blue assay	ic50	0.1200	uM
(2S)-2-amino-4-[3-methyl-4-[3-(trifluoromethyl)phenyl]anilino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.1300	uM
1-[(3,4-dimethoxyphenyl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-4-methylpiperazine	2105513: Positive allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ec50	0.1320	uM
(2S)-2-amino-4-[(7-chloro-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.1500	uM
(2S)-2-amino-4-[4-(3-chloro-4-fluorophenyl)-2-ethylanilino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.2000	uM
(2S)-2-amino-4-[(6,8-dichloro-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.2000	uM
(2S)-2-amino-4-(9H-fluoren-2-ylamino)-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.3000	uM
2-amino-4-(2-methyl-4-phenylanilino)-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.3000	uM
(2S)-2-amino-4-[(7-bromo-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.3000	uM
(2S)-2-amino-3-[(4-chlorophenyl)sulfonylamino]butanedioic acid	1321948: Inhibition of [3H]-D-Asp uptake at human EAAT1 expressed in HEK293 cells measured after 3 mins by TopCount method	ic50	0.3162	uM
2-amino-4-methyl-7-naphthalen-1-yl-5-oxo-4,6,7,8-tetrahydrochromene-3-carbonitrile	517799: Inhibition of human EAAT1 expressed in HEK293 cells by [3H]D-Asp uptake assay	ic50	0.3388	uM
N-[2-(4-chlorophenyl)ethyl]-2-(4-methylpiperazin-1-yl)-2-pyridin-3-ylacetamide	2105511: Negative allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ic50	0.3440	uM
(2S)-2-amino-3-[(4-bromophenyl)sulfonylamino]butanedioic acid	1321948: Inhibition of [3H]-D-Asp uptake at human EAAT1 expressed in HEK293 cells measured after 3 mins by TopCount method	ic50	0.3500	uM
(2S,3S)-2-amino-3-[[1-(4-methylphenyl)sulfonyl-3-[4-(trifluoromethyl)phenyl]indol-6-yl]methoxy]butanedioic acid;2,2,2-trifluoroacetic acid	1725865: Inhibition of human EAAT1 transfected in HEK293 cells assessed as inhibition of [3H]-D-aspartate uptake incubated for 4 mins by TopCount scintillation counting analysis	ic50	0.3700	uM
(2S)-2-amino-3-[(4-methylphenyl)sulfonylamino]butanedioic acid	1321948: Inhibition of [3H]-D-Asp uptake at human EAAT1 expressed in HEK293 cells measured after 3 mins by TopCount method	ic50	0.3800	uM
(2S)-2-amino-4-[4-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)anilino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.4000	uM
(2S,3S)-2-amino-3-(cyclohexylmethoxy)butanedioic acid	1356069: Inhibition of human EAAT1 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.6200	uM
2-amino-4-[(10-ethylphenoxazin-2-yl)amino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.7000	uM
(2S)-2-amino-4-[4-(3,4-dichlorophenyl)-3-methylanilino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	0.7000	uM
(2S,3S)-2-amino-3-[[1-(4-methylphenyl)sulfonyl-3-thiophen-3-ylindol-6-yl]methoxy]butanedioic acid;2,2,2-trifluoroacetic acid	1725865: Inhibition of human EAAT1 transfected in HEK293 cells assessed as inhibition of [3H]-D-aspartate uptake incubated for 4 mins by TopCount scintillation counting analysis	ic50	0.7079	uM
1-[(1-benzyltetrazol-5-yl)-pyridin-3-ylmethyl]piperazine	2105511: Negative allosteric modulation of EAAT1 (unknown origin) transfected in African green monkey COS-7 cells assessed as increase in glutamate uptake preincubated for 10 mins followed by 3-H-L-glutamate addition and measured after 10 mins by scintillation counter analysis	ic50	0.7160	uM
(2S)-2-amino-3-[(3,4-difluorophenyl)sulfonylamino]butanedioic acid	1321948: Inhibition of [3H]-D-Asp uptake at human EAAT1 expressed in HEK293 cells measured after 3 mins by TopCount method	ic50	0.7943	uM
(2S,3S)-2-amino-3-(benzenesulfonamido)butanedioic acid	1321948: Inhibition of [3H]-D-Asp uptake at human EAAT1 expressed in HEK293 cells measured after 3 mins by TopCount method	ic50	0.7943	uM
(2S)-2-amino-4-[4-(2-bromo-4,5-difluorophenoxy)anilino]-4-oxobutanoic acid	1356069: Inhibition of human EAAT1 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.8511	uM
(2S,3S)-2-amino-3-[[1-(4-methylphenyl)sulfonyl-3-phenylindol-6-yl]methoxy]butanedioic acid;2,2,2-trifluoroacetic acid	1725865: Inhibition of human EAAT1 transfected in HEK293 cells assessed as inhibition of [3H]-D-aspartate uptake incubated for 4 mins by TopCount scintillation counting analysis	ic50	1.0000	uM
(2S)-2-amino-4-[(7,8-difluorodibenzofuran-2-yl)amino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	1.0000	uM
(2S)-2-amino-4-[2-methyl-4-[3-(trifluoromethyl)phenyl]anilino]-4-oxobutanoic acid	255072: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 1	ic50	1.0000	uM
2-amino-3-phenylmethoxybutanedioic acid	1725865: Inhibition of human EAAT1 transfected in HEK293 cells assessed as inhibition of [3H]-D-aspartate uptake incubated for 4 mins by TopCount scintillation counting analysis	ic50	1.1749	uM
(2S,3S)-2-amino-3-(thiophen-2-ylmethoxy)butanedioic acid	1356069: Inhibition of human EAAT1 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	1.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases reaction	8
sodium arsenite	decreases expression, increases expression	4
trichostatin A	increases expression, affects cotreatment	3
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
bisphenol A	affects expression, increases expression	2
mono-(2-ethylhexyl)phthalate	decreases expression, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
sulforaphane	increases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	decreases expression, decreases reaction	1
coumarin	decreases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
belinostat	affects cotreatment, increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
picoxystrobin	increases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Amiodarone	increases expression	1

ChEMBL screening assays

47 unique, capped per target: 38 binding, 9 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1016585	Binding	Inhibition of glutamate-induced depolarization in human EAAT1 expressed in HEK293 cells by FMP assay	Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2. — J Med Chem
CHEMBL5209609	Functional	Substrate uptake by the Excitatory Amino Acid Transporter 1 (EAAT1, SLC1A3) as assessed by the fluorescent FLIPR membrane potential dye in HEK-293 JumpIN-SLC1A3 cells (PubChem AID: 1745864)	Membrane potential based transport assay for SLC1A3 using HEK293 JumpIn SLC1A3 OE cells

Cellosaurus cell lines

10 cell lines: 5 transformed cell line, 4 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C0RX	HEK293-CNG-Slc1a3	Transformed cell line	Female
CVCL_C0ST	ACTOne GRM2	Transformed cell line	Female
CVCL_C0SU	ACTOne GRM4	Transformed cell line	Female
CVCL_C0SV	ACTOne GRM7	Transformed cell line	Female
CVCL_C0SW	ACTOne GRM8	Transformed cell line	Female
CVCL_D4IN	HCT116-SLC1A3-KO-c2	Cancer cell line	Male
CVCL_D4IP	HCT116-SLC1A3-KO-c6	Cancer cell line	Male
CVCL_E4VB	KOLF2.1J SLC1A3 15.4kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_TL83	HAP1 SLC1A3 (-) 1	Cancer cell line	Male
CVCL_TL84	HAP1 SLC1A3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford