SLC1A1

Summary

SLC1A1 (solute carrier family 1 member 1, HGNC:10939) is a protein-coding gene on chromosome 9p24.2, encoding Excitatory amino acid transporter 3 (P43005). 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 the high-affinity glutamate transporters that play an essential role in transporting glutamate across plasma membranes. In brain, these transporters are crucial in terminating the postsynaptic action of the neurotransmitter glutamate, and in maintaining extracellular glutamate concentrations below neurotoxic levels. This transporter also transports aspartate, and mutations in this gene are thought to cause dicarboxylicamino aciduria, also known as glutamate-aspartate transport defect.

Source: NCBI Gene 6505 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dicarboxylic aminoaciduria (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 253 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 6
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004170

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10939
Approved symbol	SLC1A1
Name	solute carrier family 1 member 1
Location	9p24.2
Locus type	gene with protein product
Status	Approved
Aliases	EAAC1, EAAT3, hEAAC1
Ensembl gene	ENSG00000106688
Ensembl biotype	protein_coding
OMIM	133550
Entrez	6505

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000262352, ENST00000422398, ENST00000490167, ENST00000931882, ENST00000954075

RefSeq mRNA: 1 — MANE Select: NM_004170 NM_004170

CCDS: CCDS6452

Canonical transcript exons

ENST00000262352 — 12 exons

Exon	Start	End
ENSE00000687675	4573907	4574014
ENSE00000687677	4576001	4576123
ENSE00000687679	4576569	4576763
ENSE00000687682	4583038	4583172
ENSE00001121069	4585312	4587469
ENSE00001593171	4544567	4544707
ENSE00001617496	4566047	4566089
ENSE00001735786	4567669	4567767
ENSE00001774455	4572204	4572388
ENSE00002250590	4490468	4490770
ENSE00003519938	4564344	4564458
ENSE00003589842	4561449	4561541

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 98.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.6987 / max 134.8511, expressed in 1145 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95898	2.2407	828
95897	1.6203	741
95899	0.8574	342
95896	0.7322	279
95901	0.0781	45
95902	0.0651	35
95900	0.0622	28
205415	0.0425	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	98.93	gold quality
jejunal mucosa	UBERON:0000399	98.88	gold quality
ileal mucosa	UBERON:0000331	98.04	gold quality
nephron tubule	UBERON:0001231	95.90	gold quality
pancreatic ductal cell	CL:0002079	95.23	gold quality
duodenum	UBERON:0002114	93.70	gold quality
kidney epithelium	UBERON:0004819	93.57	gold quality
decidua	UBERON:0002450	92.37	gold quality
lower lobe of lung	UBERON:0008949	92.12	gold quality
postcentral gyrus	UBERON:0002581	92.05	gold quality
endothelial cell	CL:0000115	92.00	gold quality
superior frontal gyrus	UBERON:0002661	91.32	gold quality
caput epididymis	UBERON:0004358	91.14	gold quality
gall bladder	UBERON:0002110	91.13	gold quality
colonic mucosa	UBERON:0000317	91.10	gold quality
renal glomerulus	UBERON:0000074	91.07	gold quality
metanephric glomerulus	UBERON:0004736	90.81	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.77	gold quality
liver	UBERON:0002107	90.73	gold quality
middle temporal gyrus	UBERON:0002771	90.73	gold quality
parietal lobe	UBERON:0001872	90.26	gold quality
cortical plate	UBERON:0005343	90.26	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.20	gold quality
right lobe of liver	UBERON:0001114	90.16	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.08	gold quality
orbitofrontal cortex	UBERON:0004167	90.07	gold quality
adult organism	UBERON:0007023	89.84	gold quality
entorhinal cortex	UBERON:0002728	89.78	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.63	gold quality
palpebral conjunctiva	UBERON:0001812	88.54	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	45.22
E-MTAB-6678	yes	8.88
E-ANND-3	yes	5.28
E-MTAB-6058	no	30.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RFX1

miRNA regulators (miRDB)

134 targeting SLC1A1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-5696	99.98	72.36	4487
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-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627

Literature-anchored findings (GeneRIF, showing 40)

• Dynamic equilibrium between coupled and uncoupled modes of a neuronal glutamate transporter (PMID:11823462)
• data show specific localization of glutamate transporters EAAT1, EAAT2 and EAAT3 in the human placenta during development (PMID:15135231)
• EAAT3 has a big extracellular vestibule, but does not undergo a large-scale motion to another state. Short channels connect the intracellular solution to the vestibule. Small conformational changes & glutamate uptake, occur independently in each subunit. (PMID:15716409)
• 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)
• EAAT3 is expressed from mRNA and transports glutamate in platelets. (PMID:16198020)
• Asp-367, but not Asp-454, is involved in coordinating the bound Na(+) in the glutamate-free transporter form of the glutamate transporter EAAC1 (PMID:16478724)
• EAAC1 is the high-affinity L-aspartate transporter for aspartate uptake & accumulation in prostate cells. Regulation of EAAC1 expression & L-aspartate transport by testosterone & prolactin is consistent with their regulation of citrate production. (PMID:16566829)
• a highly regulated process of EAAC1/EAAT3 activity/expression may have implications in the physiopathology of major diseases affecting EAA brain signalling–REVIEW (PMID:16800850)
• EAAC1 transgenic mice exhibit significantly less neuronal death following axotomy, compared to EAAC1 wild-type mice that lose approximately 50% of neurons in the injured hypoglossal nuclei. (PMID:16858406)
• SLC1A1 is unlikely to be a major susceptibility gene for schizophrenia in the Japanese population. (PMID:17221839)
• Coexpression of wild-type neuronal glutamate transporter EAAT3 with mutated subunits results in transport activity consistent with two distinct noninteracting populations of transporters. (PMID:17360916)
• Independent, rather than cooperative anion conductance gating significantly alters predictions of the influence that EAAT3-mediated anion currents will have on synaptic transmission at low glutamate concentrations. (PMID:17360917)
• analysis of the 4B-4C loop in the human glutamate transporter excitatory amino acid transporter 3 (PMID:17588938)
• Results suggest that two conformational changes accompany glutamate translocation and at least one conformational change accompanies the relocation of the empty Eaac1 transporter. (PMID:17630698)
• These results show GTRAP3-18 to negatively and dominantly regulate cellular GSH content via interaction with EAAC1 at the plasma membrane. (PMID:17646425)
• Single nucleotide polymorphism markers and related haplotypes of SLC1A1 glutamate transporter gene is associated with obsessive-compulsive disorder (PMID:17894418)
• propose a kinetic model, suggesting that glutamate association of EAAC1, with its extracellular binding site as well as dissociation from its intracellular binding site, precedes association and dissociation of at least one Na(+) ion (PMID:17991780)
• RTN2B functions as a positive regulator in the delivery of EAAC1 from the ER to the cell surface. (PMID:18096700)
• Expression of GTRAP3-18 delays the ER exit of EAAC1, as well as other members of the excitatory amino acid transporter family. (PMID:18167356)
• Potential relationship between SLC1A1 and a putative genetic linkage region on chromosome 14q to obsessive-compulsive disorder with compulsive hoarding. (PMID:18286588)
• findings suggest aberrant EAAC1 expression is associated with Alzheimer disease(AD)related neuropathology & intracellular accumulation of detergent-insoluble EAAC1 is a feature of complex biochemical lesions in AD that include altered protein solubility (PMID:18624794)
• Our study indicated a strong association signal with the single nucleotide polymorphism, SNP RS301443 (P-value = 0.000067 and obsessive complusive disorder in a family based association study. (PMID:19152386)
• Our case-control data corroborate previous smaller family-based studies that indicated that SLC1A1 is a susceptibility locus for OCD. (PMID:19349310)
• fAMILY-BASED association test revealed nominally significant association between autism, and one SNP under a recessive model. (PMID:19360657)
• SLC1A1 alleles may have a role in obsessive-compulsive disorder (PMID:19569082)
• PIP5K2A is a novel signaling element in the regulation of EAAT3 activity (PMID:19644675)
• association of SNP rs301430 with severity of repetitive behaviors and anxiety in autism spectrum disorder (PMID:20155310)
• analysis of cation binding to the glutamate transporter EAAC1 probed with mutation of the conserved amino acid residue Thr10 (PMID:20378543)
• the side chain of EAAC1 Met-367 fulfills a steric role in the positioning of the substrate in the binding pocket in a step subsequent to its initial binding (PMID:20424168)
• suggests that T370S also alters the cation selectivity of this cation-binding site, as expected if T370 forms part of a cation-binding site in EAAT3. (PMID:20634426)
• Cysteine uptake by EAAC1 is important for zinc homeostasis and neuronal antioxidant function following transient cerebral ischemia. (PMID:21084597)
• SLC1A1 mutations leading to substitution of arginine to tryptophan at position 445 (R445W) and deletion of isoleucine at position 395 (I395del) cause dicarboxylic aminoaciduria, an autosomal recessive disorder of urinary glutamate and aspartate transport (PMID:21123949)
• genotyped an additional 111 SNPs in or near SLC1A1, covering from 9 kb upstream to 84 kb downstream of the gene at average spacing of 1.7 kb per SNP, and conducted family-based association analyses in 1,576 participants in 377 families (PMID:21445956)
• This study provides suggestive evidence that DLGAP3 and its interactive effect with SLC1A1 might be involved in susceptibility to developing OC symptoms in schizophrenia patients receiving AAP treatment. (PMID:21990008)
• These findings suggest the involvement of SLC1A1 in the pathogenesis of schizophrenia. (PMID:22095641)
• Individuals with schizophrenia carrying at least one C allele of rs35753505 (SNP8NRG221533) show decreased expression of SLC1A6 in the molecular layer of both cerebellar hemispheres, compared to individuals homozygous for the T allele. (PMID:22424243)
• interaction of NCX1 and EAAC1 transporters leads to glutamate-enhanced ATP production in brain mitochondria (PMID:22479505)
• mTOR is a novel powerful regulator of EAAT3 and may thus contribute to protection against neuroexcitotoxicity. (PMID:22483750)
• Three single nucleotide polymorphisms in SLC1A1 (rs2228622, rs3780412 and rs3780413), which had been associated with second-generation antipsychotic agents-induced obsessive-compulsive symptoms, were investigated. (PMID:22531293)
• Neutralizing aspartate 83 modifies substrate translocation of excitatory amino acid transporter 3 (EAAT3) glutamate transporters. (PMID:22532568)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc1a1	ENSDARG00000020212
mus_musculus	Slc1a1	ENSMUSG00000024935
rattus_norvegicus	Slc1a1	ENSRNOG00000014816

Paralogs (6): SLC1A3 (ENSG00000079215), SLC1A6 (ENSG00000105143), SLC1A5 (ENSG00000105281), SLC1A2 (ENSG00000110436), SLC1A4 (ENSG00000115902), SLC1A7 (ENSG00000162383)

Protein

Protein identifiers

Excitatory amino acid transporter 3 — P43005 (reviewed: P43005)

Alternative names: Excitatory amino-acid carrier 1, Neuronal and epithelial glutamate transporter, Sodium-dependent glutamate/aspartate transporter 3, Solute carrier family 1 member 1

All UniProt accessions (2): P43005, H0Y7R2

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. Can also transport L-cysteine. 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 an important role in L-glutamate and L-aspartate reabsorption in renal tubuli. 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. Contributes to glutathione biosynthesis and protection against oxidative stress via its role in L-glutamate and L-cysteine transport. Negatively regulated by ARL6IP5.

Subunit / interactions. Homotrimer. Interacts with ARL6IP5. Interacts with RTN2 (via N-terminus); the interaction promotes cell surface expression of SLC1A1. Interacts with SORCS2; this interaction is important for normal expression at the cell membrane.

Subcellular location. Cell membrane. Apical cell membrane. Synapse. Synaptosome. Early endosome membrane. Late endosome membrane. Recycling endosome membrane.

Tissue specificity. Expressed in all tissues tested including liver, muscle, testis, ovary, retinoblastoma cell line, neurons and brain (in which there was dense expression in substantia nigra, red nucleus, hippocampus and in cerebral cortical layers).

Post-translational modifications. Glycosylated.

Disease relevance. Dicarboxylic aminoaciduria (DCBXA) [MIM:222730] An autosomal recessive disorder characterized by abnormal excretion of urinary glutamate and aspartate, resulting from the incomplete reabsorption of anionic amino acids from the glomerular filtrate in the kidney. It can be associated with intellectual disability. The disease is caused by variants affecting the gene represented in this entry. Schizophrenia 18 (SCZD18) [MIM:615232] A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. Disease susceptibility is associated with variants affecting the gene represented in this entry. A deletion at the chromosome 9p24.2 locus, including SLC1A1, has been identified in patients with psychotic disorders. This 84 kb deletion is immediately upstream of the SLC1A1 gene in a regulatory region that contains the full native promoter sequence, extends through exon 1 of the SLC1A1 mRNA, co-segregates with disease in an extended 5-generation pedigree and increases disease risk more than 18-fold for family members.

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.

Similarity. Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A1 subfamily.

RefSeq proteins (1): NP_004161* (*=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), 4 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)
• K(+)(in) + L-cysteine(out) + 3 Na(+)(out) + H(+)(out) = K(+)(out) + L-cysteine(in) + 3 Na(+)(in) + H(+)(in) (RHEA:82559)

UniProt features (93 total): helix 25, binding site 19, topological domain 11, sequence conflict 9, transmembrane region 8, turn 5, sequence variant 4, strand 4, glycosylation site 3, intramembrane region 2, modified residue 2, chain 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
8CUA	ELECTRON MICROSCOPY	2.44
8CV2	ELECTRON MICROSCOPY	2.44
8CUI	ELECTRON MICROSCOPY	2.55
9P4Y	ELECTRON MICROSCOPY	2.56
9D68	ELECTRON MICROSCOPY	2.58
9D6A	ELECTRON MICROSCOPY	2.6
9P4X	ELECTRON MICROSCOPY	2.76
8CTC	ELECTRON MICROSCOPY	2.8
9P4Z	ELECTRON MICROSCOPY	2.83
6X2L	ELECTRON MICROSCOPY	2.85
9D67	ELECTRON MICROSCOPY	2.87
8CUD	ELECTRON MICROSCOPY	2.94
9D66	ELECTRON MICROSCOPY	2.98
9D69	ELECTRON MICROSCOPY	2.99
6X2Z	ELECTRON MICROSCOPY	3.03
6X3F	ELECTRON MICROSCOPY	3.03
8CUJ	ELECTRON MICROSCOPY	3.04
8CV3	ELECTRON MICROSCOPY	3.04
6S3Q	ELECTRON MICROSCOPY	3.34
7NSG	ELECTRON MICROSCOPY	3.34
6X3E	ELECTRON MICROSCOPY	3.42
8CTD	ELECTRON MICROSCOPY	3.42

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43005-F1	80.05	0.50

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 (19): 98; 101; 102; 331; 333; 362; 364; 366; 368; 370; 405; 406 …

Post-translational modifications (2): 517, 522

Glycosylation sites (3): 43, 178, 195

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-210500	Glutamate Neurotransmitter Release Cycle
R-HSA-5619067	Defective SLC1A1 is implicated in schizophrenia 18 (SCZD18) and dicarboxylic aminoaciduria (DCBXA)
R-HSA-9958863	SLC-mediated transport of amino acids
R-HSA-425393

MSigDB gene sets: 419 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MEMORY, RNGTGGGC_UNKNOWN, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_COGNITION, MODULE_274, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_COCAINE, GOBP_RESPONSE_TO_AMINE, GAANYNYGACNY_UNKNOWN, GOBP_RESPONSE_TO_PEPTIDE, GOBP_TRANSITION_METAL_ION_TRANSPORT

GO Biological Process (67): behavioral fear response (GO:0001662), response to amphetamine (GO:0001975), glutathione biosynthetic process (GO:0006750), superoxide metabolic process (GO:0006801), monoatomic ion transport (GO:0006811), neurotransmitter transport (GO:0006836), intracellular zinc ion homeostasis (GO:0006882), G protein-coupled dopamine receptor signaling pathway (GO:0007212), glutamate receptor signaling pathway (GO:0007215), chemical synaptic transmission (GO:0007268), brain development (GO:0007420), memory (GO:0007613), grooming behavior (GO:0007625), locomotory behavior (GO:0007626), response to xenobiotic stimulus (GO:0009410), positive regulation of heart rate (GO:0010460), gene expression (GO:0010467), retina layer formation (GO:0010842), L-glutamate transmembrane transport (GO:0015813), cytokine-mediated signaling pathway (GO:0019221), neurogenesis (GO:0022008), adult behavior (GO:0030534), cellular response to oxidative stress (GO:0034599), maintenance of blood-brain barrier (GO:0035633), response to decreased oxygen levels (GO:0036293), dopamine metabolic process (GO:0042417), L-cysteine transport (GO:0042883), response to morphine (GO:0043278), negative regulation of neuron apoptotic process (GO:0043524), blood vessel morphogenesis (GO:0048514), response to axon injury (GO:0048678), synapse organization (GO:0050808), L-glutamate import (GO:0051938), righting reflex (GO:0060013), heart contraction (GO:0060047), long-term synaptic potentiation (GO:0060291), motor behavior (GO:0061744), transepithelial transport (GO:0070633), D-aspartate transmembrane transport (GO:0070777), L-aspartate transmembrane transport (GO:0070778)

GO Molecular Function (13): monoatomic anion channel activity (GO:0005253), L-glutamate transmembrane transporter activity (GO:0005313), high-affinity L-glutamate transmembrane transporter activity (GO:0005314), chloride transmembrane transporter activity (GO:0015108), L-aspartate transmembrane transporter activity (GO:0015183), glutamate:sodium symporter activity (GO:0015501), L-cysteine transmembrane transporter activity (GO:0033229), identical protein binding (GO:0042802), metal ion binding (GO:0046872), D-aspartate transmembrane transporter activity (GO:0140010), protein binding (GO:0005515), L-amino acid transmembrane transporter activity (GO:0015179), symporter activity (GO:0015293)

GO Cellular Component (33): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), apical plasma membrane (GO:0016324), axon (GO:0030424), dendrite (GO:0030425), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), asymmetric synapse (GO:0032279), neuronal cell body (GO:0043025), synaptic cleft (GO:0043083), dendritic spine (GO:0043197), dendritic shaft (GO:0043198), perikaryon (GO:0043204), axon terminus (GO:0043679), membrane raft (GO:0045121), apical part of cell (GO:0045177), synapse (GO:0045202), recycling endosome (GO:0055037), recycling endosome membrane (GO:0055038), extracellular exosome (GO:0070062), cell periphery (GO:0071944), glial cell projection (GO:0097386), apical dendrite (GO:0097440), Schaffer collateral - CA1 synapse (GO:0098685), presynapse (GO:0098793), perisynaptic space (GO:0099544), distal dendrite (GO:0150002), proximal dendrite (GO:1990635), cytoplasm (GO:0005737), endosome (GO:0005768), vesicle (GO:0031982), neuron projection (GO:0043005)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
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	6
L-amino acid transmembrane transporter activity	3
endosome membrane	3
transport	2
cell surface receptor signaling pathway	2
behavior	2
L-alpha-amino acid transmembrane transport	2
monoatomic anion transmembrane transporter activity	2
acidic amino acid transmembrane transporter activity	2
C4-dicarboxylate transmembrane transporter activity	2
neuron projection	2
dendrite	2
behavioral defense response	1
fear response	1
response to amine	1
glutathione metabolic process	1
nonribosomal peptide biosynthetic process	1
modified amino acid biosynthetic process	1
sulfur compound biosynthetic process	1
reactive oxygen species metabolic process	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
synaptic transmission, dopaminergic	1
G protein-coupled receptor signaling pathway	1
cellular response to dopamine	1
glutamate receptor activity	1
anterograde trans-synaptic signaling	1
central nervous system development	1
animal organ development	1
head development	1
learning or memory	1
response to chemical	1
regulation of heart rate	1
positive regulation of heart contraction	1
macromolecule biosynthetic process	1
neural retina development	1
anatomical structure formation involved in morphogenesis	1
retina morphogenesis in camera-type eye	1
L-glutamate import	1
cellular response to cytokine stimulus	1

Protein interactions and networks

STRING

1822 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC1A1	ARL6IP5	O75915	939
SLC1A1	ATP1B3	P54709	787
SLC1A1	PAIP2B	Q9ULR5	761
SLC1A1	DLGAP3	O95886	746
SLC1A1	SLC15A1	P46059	718
SLC1A1	SLC3A1	Q07837	715
SLC1A1	GLIS3	Q8NEA6	713
SLC1A1	ADCY6	O43306	703
SLC1A1	SLC6A19	Q695T7	670
SLC1A1	SLC7A5	Q01650	645
SLC1A1	MPDZ	O75970	644
SLC1A1	SLC7A7	Q9UM01	633
SLC1A1	SLC38A2	Q96QD8	629
SLC1A1	SLC7A9	P82251	626
SLC1A1	GLUL	P15104	626

IntAct

205 interactions, top by confidence:

A	B	Type	Score
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
RNF5	SLC1A1	psi-mi:“MI:0915”(physical association)	0.720
SLC1A1	RNF5	psi-mi:“MI:0915”(physical association)	0.720
LDLRAD1	SLC1A1	psi-mi:“MI:0915”(physical association)	0.670
SLC1A1	LDLRAD1	psi-mi:“MI:0915”(physical association)	0.670
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
NUMB	SLC1A1	psi-mi:“MI:0914”(association)	0.640
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
DLG1	SLC1A1	psi-mi:“MI:0407”(direct interaction)	0.620
SLC1A1	DLG1	psi-mi:“MI:0407”(direct interaction)	0.620
SLC1A1	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.590
SLC35A1	SLC1A1	psi-mi:“MI:0915”(physical association)	0.560
	SLC1A1	psi-mi:“MI:0915”(physical association)	0.560
SLC1A1	FAM209A	psi-mi:“MI:0915”(physical association)	0.560
SLC1A1	SLC35A1	psi-mi:“MI:0915”(physical association)	0.560
SLC1A1	FXYD3	psi-mi:“MI:0915”(physical association)	0.560
SLC1A1	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
SLC1A1	TMEM179B	psi-mi:“MI:0915”(physical association)	0.560
SLC1A1	SYNPR	psi-mi:“MI:0915”(physical association)	0.560
PAGE1	SLC1A1	psi-mi:“MI:0915”(physical association)	0.560
NRN1	SLC1A1	psi-mi:“MI:0914”(association)	0.530
SLC1A1	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (282): SLC1A1 (Two-hybrid), LDLRAD1 (Two-hybrid), SLC1A1 (Affinity Capture-MS), SLC1A1 (Affinity Capture-MS), SLC1A1 (Two-hybrid), NUMBL (Affinity Capture-MS), CC2D1A (Affinity Capture-MS), C7orf55 (Affinity Capture-MS), SNX3 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), GOLGA7 (Affinity Capture-MS), ORMDL3 (Affinity Capture-MS), NDFIP1 (Affinity Capture-MS), SLC1A1 (Affinity Capture-MS), PXMP2 (Affinity Capture-MS)

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

2 interactions.

A	Effect	B	Mechanism
SLC1A1	“up-regulates quantity”	“glutamic acid”	relocalization
CAV1	“down-regulates activity”	SLC1A1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 149 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	33.6×	2e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	32.0×	2e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	32.0×	2e-05
Assembly and cell surface presentation of NMDA receptors	10	29.9×	1e-10
Dopamine Neurotransmitter Release Cycle	5	29.2×	3e-05
Long-term potentiation	5	28.0×	3e-05
Neurexins and neuroligins	11	25.5×	1e-10
Protein-protein interactions at synapses	7	21.9×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	43.0×	1e-11
protein localization to synapse	6	34.0×	4e-06
receptor clustering	7	32.4×	5e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	6	22.0×	3e-05
protein-containing complex assembly	10	8.4×	3e-05
cell-cell adhesion	10	7.5×	8e-05
establishment of localization in cell	6	7.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	160
Likely benign	22
Benign	44

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
3063063	GRCh37/hg19 9p24.2(chr9:4386287-4561374)x1	Pathogenic
3063065	GRCh37/hg19 9p24.2(chr9:4339192-4523382)x1	Pathogenic
687614	GRCh37/hg19 9p24.2(chr9:4438880-4528118)x1	Pathogenic
224823	NM_004170.6(SLC1A1):c.1264G>A (p.Val422Met)	Likely pathogenic

SpliceAI

1961 predictions. Top by Δscore:

Variant	Effect	Δscore
9:4567643:T:A	acceptor_gain	1.0000
9:4567649:T:A	acceptor_gain	1.0000
9:4567660:A:AG	acceptor_gain	1.0000
9:4567660:AACAT:A	acceptor_gain	1.0000
9:4567661:A:G	acceptor_gain	1.0000
9:4567662:C:G	acceptor_gain	1.0000
9:4567663:A:AG	acceptor_gain	1.0000
9:4567663:AT:A	acceptor_gain	1.0000
9:4567664:T:G	acceptor_gain	1.0000
9:4567664:T:TA	acceptor_gain	1.0000
9:4567664:TGCA:T	acceptor_loss	1.0000
9:4567665:GCAG:G	acceptor_loss	1.0000
9:4567666:CA:C	acceptor_loss	1.0000
9:4567667:A:AG	acceptor_gain	1.0000
9:4567667:AGTA:A	acceptor_loss	1.0000
9:4567668:G:GA	acceptor_gain	1.0000
9:4567668:GT:G	acceptor_gain	1.0000
9:4567668:GTA:G	acceptor_gain	1.0000
9:4567668:GTAC:G	acceptor_gain	1.0000
9:4567668:GTACA:G	acceptor_gain	1.0000
9:4567763:CCAAG:C	donor_loss	1.0000
9:4567764:CAAG:C	donor_loss	1.0000
9:4567765:AAGGT:A	donor_loss	1.0000
9:4567766:AGG:A	donor_loss	1.0000
9:4567769:T:A	donor_loss	1.0000
9:4572188:T:A	acceptor_gain	1.0000
9:4572202:A:AG	acceptor_gain	1.0000
9:4572203:G:GG	acceptor_gain	1.0000
9:4572203:GAAC:G	acceptor_gain	1.0000
9:4572385:TGTGG:T	donor_loss	1.0000

AlphaMissense

3434 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:4576675:G:T	G369W	1.000
9:4576676:G:A	G369E	1.000
9:4561541:G:C	G109R	0.999
9:4572261:G:C	G214R	0.999
9:4576671:G:A	M367I	0.999
9:4576671:G:C	M367I	0.999
9:4576671:G:T	M367I	0.999
9:4576675:G:A	G369R	0.999
9:4576675:G:C	G369R	0.999
9:4576676:G:T	G369V	0.999
9:4576708:T:C	F380L	0.999
9:4576710:T:A	F380L	0.999
9:4576710:T:G	F380L	0.999
9:4583045:G:C	A401P	0.999
9:4583046:C:A	A401D	0.999
9:4583055:C:A	A404D	0.999
9:4583163:A:T	D440V	0.999
9:4585323:G:T	R447M	0.999
9:4585336:C:A	N451K	0.999
9:4585336:C:G	N451K	0.999
9:4490770:G:C	G31R	0.998
9:4572289:G:A	G223E	0.998
9:4574013:G:T	G292W	0.998
9:4574014:G:A	G292E	0.998
9:4576652:T:A	V361D	0.998
9:4576654:G:C	G362R	0.998
9:4576655:G:A	G362D	0.998
9:4576668:C:A	N366K	0.998
9:4576668:C:G	N366K	0.998
9:4576682:C:A	A371E	0.998

dbSNP variants (sampled 300 via entrez): RS1000015156 (9:4519935 C>A,T), RS1000021310 (9:4494495 A>C), RS1000021999 (9:4498914 A>C), RS1000042285 (9:4513243 A>G,T), RS1000058620 (9:4496231 G>A), RS1000088724 (9:4494480 T>C,G), RS1000090631 (9:4526510 T>C), RS1000105979 (9:4531013 G>C), RS1000138537 (9:4559432 T>C,G), RS1000200682 (9:4521520 G>C), RS1000207574 (9:4541808 G>A,T), RS1000237094 (9:4514498 G>A,C), RS1000297388 (9:4503671 A>G), RS1000301690 (9:4555300 T>G), RS1000304993 (9:4516640 A>G)

Disease associations

OMIM: gene MIM:133550 | disease phenotypes: MIM:222730, MIM:615232

GenCC curated gene-disease

Disease	Classification	Inheritance
dicarboxylic aminoaciduria	Strong	Autosomal recessive
hot water reflex epilepsy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
dicarboxylic aminoaciduria	Limited	AR

Mondo (3): dicarboxylic aminoaciduria (MONDO:0009110), schizophrenia 18 (MONDO:0014092), hot water reflex epilepsy (MONDO:0013229)

Orphanet (1): Dicarboxylic aminoaciduria (Orphanet:2195)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000787	Nephrolithiasis
HP:0001249	Intellectual disability
HP:0003162	Fasting hypoglycemia
HP:0003355	Aminoaciduria
HP:0032401	Aspartic aciduria

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001350_7	Pancreatic cancer	5.000000e-06
GCST002097_36	Coronary artery calcification	8.000000e-06
GCST004750_27	Squamous cell lung carcinoma	6.000000e-06
GCST006292_2	Response to antipsychotic treatment in schizophrenia	2.000000e-09
GCST006294_1	Response to risperidone in schizophrenia	4.000000e-08
GCST009391_1602	Metabolite levels	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0010377	phosphatidylcholine 34:3 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536171	Dicarboxylicaminoaciduria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2721 (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 clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs301434	Efficacy	3	Selective serotonin reuptake inhibitors	Obsessive-Compulsive Disorder
rs301435	Efficacy	3	Selective serotonin reuptake inhibitors	Obsessive-Compulsive Disorder
rs3087879	Efficacy	3	Selective serotonin reuptake inhibitors	Obsessive-Compulsive Disorder

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs301434	SLC1A1, SPATA6L	3	0.00	1	Selective serotonin reuptake inhibitors
rs301435	SLC1A1, SPATA6L	3	0.00	1	Selective serotonin reuptake inhibitors
rs2228622	SLC1A1, SPATA6L		0.00	0
rs3087879	SLC1A1, SPATA6L	3	3.50	1	Selective serotonin reuptake inhibitors
rs3780412	SLC1A1, SPATA6L		0.00	0
rs3780413	SLC1A1, SPATA6L		0.00	0
rs10815019	SLC1A1, SPATA6L		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 (4 total), top 4:

Ligand	Action	Affinity	Parameter
NBI-59159	Inhibition	7.1	pIC50
[3H]ETB-TBOA	Binding	6.5	pKd
L-β-BA	Inhibition	6.1	pKi
DL-TBOA	Inhibition	5.1	pIC50

Binding affinities (BindingDB)

5 measured of 5 human assays (5 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
3-[3-Methyl-4-(4-chlorophenyl)benzoylamino]alanine	KI	190 nM
WAY-213394	KI	1970 nM
WAY-855	KI	2200 nM
WAY-212922	KI	3430 nM
N-[4-(2-BROMO-4,5-DIFLUOROPHENOXY)PHENYL]-L-ASPARAGINE	KI	5000 nM

ChEMBL bioactivities

138 potent at pChembl≥5 of 208 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	EC50	0.2	nM	CHEMBL5593916
8.81	EC50	1.55	nM	CHEMBL5564905
8.60	EC50	2.5	nM	CHEMBL5594077
8.37	EC50	4.3	nM	CHEMBL5583680
7.47	IC50	34	nM	CHEMBL5409124
7.30	IC50	50	nM	CHEMBL2113115
7.29	Ki	51	nM	GLUTAMIC ACID
7.26	IC50	55	nM	CHEMBL4177507
7.26	IC50	54.95	nM	CHEMBL4177507
7.03	IC50	94	nM	CHEMBL4176482
7.03	IC50	93.33	nM	CHEMBL4176482
6.98	IC50	104.7	nM	CHEMBL4176427
6.96	IC50	110	nM	CHEMBL4176427
6.93	IC50	117.5	nM	CHEMBL1257519
6.92	IC50	120	nM	CHEMBL1257519
6.90	IC50	125	nM	CHEMBL5573743
6.89	IC50	130	nM	CHEMBL4165811
6.89	IC50	128.8	nM	CHEMBL4165811
6.88	EC50	132	nM	CHEMBL1393473
6.85	IC50	140	nM	CHEMBL2113112
6.70	IC50	200	nM	CHEMBL2113116
6.54	IC50	290	nM	CHEMBL4173045
6.54	IC50	288.4	nM	CHEMBL4173045
6.52	IC50	300	nM	CHEMBL2113111
6.52	IC50	300	nM	CHEMBL1257519
6.38	IC50	420	nM	CHEMBL1628570
6.35	IC50	450	nM	CHEMBL2113118
6.30	IC50	500	nM	CHEMBL2113122
6.28	IC50	530	nM	CHEMBL4162363
6.28	IC50	524.8	nM	CHEMBL4162363
6.22	IC50	600	nM	CHEMBL424838
6.22	IC50	600	nM	CHEMBL2113113
6.22	IC50	600	nM	CHEMBL2113123
6.19	IC50	650	nM	CHEMBL2113117
6.10	IC50	800	nM	CHEMBL458273
6.08	IC50	840	nM	CHEMBL4166966
6.07	IC50	850	nM	CHEMBL2113126
6.07	IC50	860	nM	CHEMBL4169695
6.07	IC50	851.1	nM	CHEMBL4166966
6.06	IC50	871	nM	CHEMBL4169695
6.01	IC50	977.2	nM	CHEMBL3960774
6.00	IC50	1000	nM	CHEMBL373283
6.00	IC50	1000	nM	CHEMBL425569
6.00	IC50	1000	nM	CHEMBL198315
6.00	IC50	1000	nM	CHEMBL3960774
6.00	Ki	1000	nM	CHEMBL446256
5.93	IC50	1175	nM	CHEMBL4163105
5.92	IC50	1202	nM	CHEMBL3937517
5.92	IC50	1200	nM	CHEMBL3937517
5.92	IC50	1200	nM	CHEMBL4163105

PubChem BioAssay actives

138 with measured affinity, of 539 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
4-[(1-benzyltetrazol-5-yl)-(4-methylpiperazin-1-yl)methyl]benzonitrile	2105512: Positive allosteric modulation of EAAT3 (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	0.0002	uM
5-[(4-methylpiperazin-1-yl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-1H-pyridin-2-one	2105512: Positive allosteric modulation of EAAT3 (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	0.0015	uM
1-[(6-fluoro-3-pyridinyl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-4-methylpiperazine	2105512: Positive allosteric modulation of EAAT3 (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	0.0025	uM
N-[2-(4-fluorophenyl)ethyl]-2-(4-methylpiperazin-1-yl)-2-pyridin-3-ylacetamide	2105512: Positive allosteric modulation of EAAT3 (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	0.0043	uM
(2S,3S)-2-amino-3-[[3-[(4-phenylbenzoyl)amino]phenyl]methoxy]butanedioic acid	2028649: Inhibition of human EAAT3 transfected in MDCK cells assessed as reduction in [14C]glutamate uptake	ic50	0.0340	uM
(2S)-2-amino-4-[(7-fluoro-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.0500	uM
glutamic acid	339909: Inhibition of [3H]D-Asp uptake at human EAAT3 in HEK293 cells	ki	0.0510	uM
(2S,3S)-2-amino-4-(9H-fluoren-2-ylamino)-4-oxo-3-phenylmethoxybutanoic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0549	uM
(2S,3S)-2-amino-4-[4-(2-bromo-4,5-difluorophenoxy)anilino]-4-oxo-3-phenylmethoxybutanoic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0933	uM
(2S,3S)-2-amino-3-[[3-[3-[4-(trifluoromethyl)phenyl]propanoylamino]phenyl]methoxy]butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.1047	uM
(2S,3S)-2-amino-3-[[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.1175	uM
N-[2-(4-chlorophenyl)ethyl]-2-(4-methylpiperazin-1-yl)-2-pyridin-3-ylacetamide	2105516: Negative allosteric modulation of EAAT3 (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	0.1250	uM
(2S,3S)-2-amino-3-[[3-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]phenyl]methoxy]butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.1288	uM
1-[(3,4-dimethoxyphenyl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-4-methylpiperazine	2105512: Positive allosteric modulation of EAAT3 (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-[3-methyl-4-[3-(trifluoromethyl)phenyl]anilino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.1400	uM
(2S)-2-amino-4-[(7-chloro-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.2000	uM
(2S,3S)-2-amino-3-[[3-[[3-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.2884	uM
(2S)-2-amino-4-[4-(3-chloro-4-fluorophenyl)-2-ethylanilino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.3000	uM
(2S)-2-amino-4-(9H-fluoren-2-ylamino)-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.4200	uM
(2S)-2-amino-4-[(6,8-dichloro-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.4500	uM
(2S)-2-amino-4-oxo-4-[4-[3-(trifluoromethyl)phenyl]anilino]butanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.5000	uM
(2S,3S)-2-amino-3-[[3-[[2-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.5248	uM
2-amino-4-(2-methyl-4-phenylanilino)-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.6000	uM
(2S)-2-amino-4-[2-methyl-4-[3-(trifluoromethyl)phenyl]anilino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.6000	uM
(2S)-2-amino-4-[4-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)anilino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.6000	uM
(2S)-2-amino-4-[(7-bromo-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.6500	uM
(2S,3S)-2-amino-3-benzylbutanedioic acid	1725870: Inhibition of human EAAT3 transfected in mouse C17.2 cells assessed as inhibition of [3H]-D-aspartate uptake incubated for 5 mins by liquid scintillation counting analysis	ic50	0.8000	uM
(2S,3S)-2-amino-3-prop-2-ynoxybutanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.8400	uM
(2S)-2-amino-4-[4-(3,4-dichlorophenyl)-3-methylanilino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	0.8500	uM
(2S,3S)-2-amino-3-(thiophen-3-ylmethoxy)butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.8600	uM
(2S)-2-amino-3-[(4-chlorophenyl)sulfonylamino]butanedioic acid	1321950: Inhibition of [3H]-D-Asp uptake at human EAAT3 expressed in HEK293 cells measured after 3 mins by TopCount method	ic50	0.9772	uM
(2S,4S)-2-amino-4-(phenylmethoxymethyl)pentanedioic acid	339909: Inhibition of [3H]D-Asp uptake at human EAAT3 in HEK293 cells	ki	1.0000	uM
2-amino-4-[3-(3-chloro-4-fluorophenyl)-4-methylanilino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	1.0000	uM
2-amino-4-[(10-ethylphenoxazin-2-yl)amino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	1.0000	uM
2-amino-4-oxo-4-(4-phenylanilino)butanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	1.0000	uM
(2S,3S)-2-amino-3-(thiophen-2-ylmethoxy)butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	1.1749	uM
(2S,3S)-2-amino-3-(benzenesulfonamido)butanedioic acid	1321950: Inhibition of [3H]-D-Asp uptake at human EAAT3 expressed in HEK293 cells measured after 3 mins by TopCount method	ic50	1.2000	uM
(2S,3S)-2-amino-3-(furan-3-ylmethoxy)butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	1.2000	uM
1-[(1-benzyltetrazol-5-yl)-pyridin-3-ylmethyl]piperazine	2105516: Negative allosteric modulation of EAAT3 (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	1.4870	uM
(2S)-2-amino-4-[4-(4-chlorophenyl)-3-methylanilino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	1.5000	uM
(2S,3S)-2-amino-3-(cyanomethoxy)butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	1.5488	uM
(2S,3S)-2-amino-3-(furan-2-ylmethoxy)butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	1.6000	uM
(2S)-2-amino-4-[(7,8-difluorodibenzofuran-2-yl)amino]-4-oxobutanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	1.8000	uM
(2S)-2-amino-4-[4-(2-bromo-4,5-difluorophenoxy)anilino]-4-oxobutanoic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	1.8621	uM
(2S)-2-amino-3-[(4-methylphenyl)sulfonylamino]butanedioic acid	1321950: Inhibition of [3H]-D-Asp uptake at human EAAT3 expressed in HEK293 cells measured after 3 mins by TopCount method	ic50	1.9000	uM
(2S)-2-amino-3-[(4-fluorophenyl)sulfonylamino]butanedioic acid	1321950: Inhibition of [3H]-D-Asp uptake at human EAAT3 expressed in HEK293 cells measured after 3 mins by TopCount method	ic50	2.0000	uM
(2S)-2-amino-4-oxo-4-[(9-oxofluoren-2-yl)amino]butanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	2.0000	uM
(2S,3S)-2-amino-3-(cyclobutylmethoxy)butanedioic acid	1356071: Inhibition of human EAAT3 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	2.1000	uM
(2S)-2-amino-4-oxo-4-[[7-(trifluoromethyl)-9H-fluoren-2-yl]amino]butanoic acid	255074: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 3	ic50	2.4000	uM
(2S,3S)-2-amino-3-[[3-[(4-methoxybenzoyl)amino]phenyl]methoxy]butanedioic acid	2028646: Inhibition of human EAAT3 transfected in African green monkey COS-1 cells assessed as reduction in [14C]glutamate uptake	ic50	2.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
Estradiol	affects cotreatment, decreases expression, increases expression	5
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
Aflatoxin B1	increases methylation, affects expression, decreases expression	3
methylmercuric chloride	decreases expression, increases expression	2
bisphenol A	affects cotreatment, increases methylation, increases expression	2
trichostatin A	increases expression	2
Cisplatin	affects cotreatment, affects expression, affects response to substance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	decreases expression, increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	increases expression, affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
terbufos	increases methylation	1
afimoxifene	decreases expression	1
cobaltous chloride	increases expression	1
tobacco tar	decreases reaction, decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
diallyl disulfide	decreases expression, decreases reaction	1
allyl sulfide	decreases expression, decreases reaction	1
dinophysistoxin 1	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	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
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
abrine	decreases expression	1

ChEMBL screening assays

50 unique, capped per target: 43 binding, 7 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1013069	Binding	Inhibition of [3H]D-Asp uptake at human EAAT3 in HEK293 cells	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
CHEMBL5209608	Functional	Substrate uptake by the Excitatory Amino Acid Transporter 3 (EAAT3, SLC1A1) as assessed by the fluorescent FLIPR membrane potential dye in HEK-293 JumpIN-SLC1A1 cells (PubChem AID: 1794812)	Membrane potential based assay for SLC1A1 using HEK-293 SLC1A1 OE cells

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4DU	HEK-SLC1A1-KO-c1	Transformed cell line	Female
CVCL_D4IL	HCT116-SLC1A1-KO-c6	Cancer cell line	Male
CVCL_D4IM	HCT116-SLC1A1-KO-c8	Cancer cell line	Male
CVCL_TL82	HAP1 SLC1A1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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