SLC1A2

Summary

SLC1A2 (solute carrier family 1 member 2, HGNC:10940) is a protein-coding gene on chromosome 11p13, encoding Excitatory amino acid transporter 2 (P43004). 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 family of solute transporter proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Improper regulation of this gene is thought to be associated with several neurological disorders. Alternatively spliced transcript variants of this gene have been identified.

Source: NCBI Gene 6506 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 41 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 14
• Clinical variants (ClinVar): 539 total — 2 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 75
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004171

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10940
Approved symbol	SLC1A2
Name	solute carrier family 1 member 2
Location	11p13
Locus type	gene with protein product
Status	Approved
Aliases	GLT-1, GLT1, EAAT2, HBGT
Ensembl gene	ENSG00000110436
Ensembl biotype	protein_coding
OMIM	600300
Entrez	6506

Gene structure

Transcript identifiers

Ensembl transcripts: 54 — 36 protein_coding, 10 protein_coding_CDS_not_defined, 7 retained_intron, 1 nonsense_mediated_decay

ENST00000278379, ENST00000395750, ENST00000395753, ENST00000449068, ENST00000464522, ENST00000479543, ENST00000531628, ENST00000606205, ENST00000642171, ENST00000642183, ENST00000642196, ENST00000642216, ENST00000642224, ENST00000642392, ENST00000642448, ENST00000642578, ENST00000642769, ENST00000643000, ENST00000643134, ENST00000643154, ENST00000643305, ENST00000643401, ENST00000643454, ENST00000643522, ENST00000644050, ENST00000644100, ENST00000644299, ENST00000644351, ENST00000644459, ENST00000644779, ENST00000644868, ENST00000645194, ENST00000645303, ENST00000645542, ENST00000645634, ENST00000645659, ENST00000645892, ENST00000645966, ENST00000645984, ENST00000646080, ENST00000646099, ENST00000646112, ENST00000646167, ENST00000646585, ENST00000646833, ENST00000646847, ENST00000647076, ENST00000647104, ENST00000647193, ENST00000647372, ENST00000901504, ENST00000901505, ENST00000901506, ENST00000901507

RefSeq mRNA: 3 — MANE Select: NM_004171 NM_001195728, NM_001252652, NM_004171

CCDS: CCDS31459, CCDS55756

Canonical transcript exons

ENST00000278379 — 11 exons

Exon	Start	End
ENSE00000710382	35315023	35315175
ENSE00000710383	35312198	35312448
ENSE00000710384	35306074	35306242
ENSE00000710385	35301519	35301645
ENSE00000710386	35292287	35292520
ENSE00000710387	35286757	35286951
ENSE00001185570	35251205	35260965
ENSE00003528997	35280867	35281001
ENSE00003673911	35265527	35265758
ENSE00003694146	35317377	35317516
ENSE00003823708	35418950	35419558

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 99.92.

FANTOM5 (CAGE): breadth broad, TPM avg 34.4260 / max 1987.6080, expressed in 326 samples.

FANTOM5 promoters (32 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119372	22.2090	119
119367	2.8807	138
119369	2.1162	115
119371	1.2917	92
119373	0.8662	90
119370	0.8208	97
119365	0.7706	104
119374	0.5813	80
119321	0.4679	86
119361	0.4190	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.92	gold quality
entorhinal cortex	UBERON:0002728	99.90	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.90	gold quality
lateral globus pallidus	UBERON:0002476	99.86	gold quality
middle temporal gyrus	UBERON:0002771	99.83	gold quality
parietal lobe	UBERON:0001872	99.76	gold quality
postcentral gyrus	UBERON:0002581	99.74	gold quality
globus pallidus	UBERON:0001875	99.67	gold quality
medial globus pallidus	UBERON:0002477	99.64	gold quality
caudate nucleus	UBERON:0001873	99.59	gold quality
nucleus accumbens	UBERON:0001882	99.59	gold quality
temporal lobe	UBERON:0001871	99.54	gold quality
superior vestibular nucleus	UBERON:0007227	99.52	gold quality
ventral tegmental area	UBERON:0002691	99.45	gold quality
substantia nigra pars compacta	UBERON:0001965	99.44	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.43	gold quality
putamen	UBERON:0001874	99.42	gold quality
amygdala	UBERON:0001876	99.38	gold quality
primary visual cortex	UBERON:0002436	99.32	gold quality
pons	UBERON:0000988	99.21	gold quality
right frontal lobe	UBERON:0002810	99.11	gold quality
occipital lobe	UBERON:0002021	99.10	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.96	gold quality
superior frontal gyrus	UBERON:0002661	98.91	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.76	gold quality
subthalamic nucleus	UBERON:0001906	98.72	gold quality
Ammon’s horn	UBERON:0001954	98.69	gold quality
telencephalon	UBERON:0001893	98.67	gold quality
cingulate cortex	UBERON:0003027	98.41	gold quality
anterior cingulate cortex	UBERON:0009835	98.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-30	yes	9366.38
E-GEOD-84465	yes	8141.80
E-HCAD-35	yes	7732.54
E-HCAD-25	yes	7389.08
E-GEOD-180759	yes	4122.43
E-GEOD-137537	yes	15.99
E-ANND-3	yes	10.80

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, CREBBP, ESR1, ESR2, HSF1, LRRFIP1, MYCN, NFKB1, NFKB, NR3C1, PAX6, PPARG, RELA, TFAP2A, YY1

miRNA regulators (miRDB)

315 targeting SLC1A2, 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-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• The inhibition of EAAT2-mediated aspartate transport by high diazepam concentrations indicates it has less importance than EAAT1 as a drug target. (PMID:11792462)
• Reentrant loop II of the GLT-1 transporter forms part of an aqueous pore, the access of which is blocked by the glutamate analogue dihydrokainate, and that sodium influences the conformation of this pore-loop. (PMID:11994293)
• Alzheimer disease-related neurodegeneration is associated with the expression of the glutamate transporter EAAT-2 in altered neurons. (PMID:12408226)
• cloning of promoter (PMID:12578975)
• HIV-1 and gp120 induce transcriptional downmodulation of the EAAT2 transporter gene in human astrocytes and coordinately attenuate glutamate transport by the cells (PMID:12890621)
• Individual fragments of the 3’-UTR varied in their effects on reporter gene expression in human astrocytes by a factor of eight to ten suggesting a complex role of the 3’-UTR in post-transcriptional regulation of EAAT2 gene expression (PMID:12950454)
• EAAT4 but not EAAT2 anion channels displays voltage-dependent gating modified by glutamate (PMID:14506254)
• NR2B was located in the midpiece of sperm, whereas GLT1 mainly existed in the head. (PMID:14662797)
• Despite increases in truncated splice variant EAAT2b immunostaining of astrocytes and neurons in amyotrophic lateral sclerosis motor cortex, functional transporter studies demonstrate a large loss of EAAT2 function. (PMID:15048885)
• data show specific localization of glutamate transporters EAAT1, EAAT2 and EAAT3 in the human placenta during development (PMID:15135231)
• Presence of alternative EAAT2 mRNA transcripts is not disease specific, nor the primary cause of reduced EAAT2 expression in hippocampal sclerosis-associated temporal lobe epilepsy patients. (PMID:15246112)
• In an inducible mammalian cell line expressing hEAAT2 the glutamate uptake currents correlate to the amount of trimeric transporters. (PMID:15265858)
• Within the retina a novel splice variant, GLT1c, is selectively and heavily expressed in the synaptic terminals of both rod- and cone-photoreceptors. (PMID:15337309)
• GLT-1 mRNA levels in medication-free schizophrenic patients are 2.5-fold higher than in controls, whereas they are normal or reduced in patients treated with antipsychotics. (PMID:15494981)
• N-myc is recruited to the EAAT2 promoter with TNFalpha (PMID:15660126)
• 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)
• caspase-3 cleavage of EAAT2 is one mechanism responsible for the impairment of glutamate uptake in mutant SOD1-linked amyotrophic lateral sclerosis (PMID:16567804)
• In conclusion, the idea is put forward of an epigenetic mode of EAAT2 regulation based on the differential methylation of the gene promoter. (PMID:17311293)
• Transient expression of EAAT2 occurs during the window of peak vulnerability for periventricular leukomalacia, suggesting that this transporter may be a major source of extracellular glutamate in ischemic injury to the cerebral white matter. (PMID:17311320)
• The regulation of EAAT2 mRNA and protein isoforms and concludes with a summary of studies showing dysregulation of EAAT2 in psychiatric and neurological disorders. (PMID:17684493)
• the -181 A/C polymorphism in the EAAT2 gene promoter affects the personality trait of reward dependence in healthy subjects (PMID:17920768)
• In this study, the expression of EAAT2 in cerebral white matter from PVL and control cases. Western blot analysis suggested an up-regulation of EAAT2 in PVL compared with control cases. (PMID:18314905)
• ceftriaxone is a potent modulator of glutamate transport in primary human fetal astrocytes through NF-kappaB-mediated EAAT2 promoter activation (PMID:18326497)
• The findings of this study suggest that glutamate homeostasis is compromised in MS and that carrying the mutation of EAAT2 may contribute to this alteration in relapsing MS. (PMID:18378006)
• Substrates and non-transportable analogues induce structural rearrangements at the extracellular entrance of the glial glutamate transporter GLT-1/EAAT2. (PMID:18658151)
• EAAT2 is critical for clearing glutamate from excitatory synapses, and is expressed selectively in astrocytes. (PMID:18838545)
• Increased glial glutamate transporter EAAT2 expression reduces visceral nociceptive response in mice. (PMID:19023027)
• Diffuse cortical changes occur independently of HIVE in AIDS. The expression of EAAT-2 by activated microglia suggests that they might exert a compensatory effect that protects neurons from glutamate neurotoxicity. (PMID:19151621)
• 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 strongly indicate that EAAT2 acts in tauopathy-related neurodegeneration, and abnormalities in glutamate transport play an important role in the pathogenesis of tauopathies. (PMID:19527721)
• SCL1A2 appears not to be a genetic risk factor for schizophrenia. (PMID:19660525)
• The Na+ coupled glutamate carrier EAAT2 is stimulated by PIKfyve, an effect requiring an intact SGK1 phosphorylation site. (PMID:19910676)
• findings establish close similarities in the regulation of GLT-1/EAAT-2 expression in rat and man and validate rat astrocytes as an assay system for studying the molecular mechanisms affecting glutamate homeostasis in the healthy and diseased human brain (PMID:19998491)
• These results suggest that a disturbance of cholesterol metabolism may contribute to loss of EAAT2 in AD. (PMID:20193040)
• An 88 amino acid tryptic peptide covering the presumed substrate binding domains HP1, TMD7, HP2, and TMD8 domains of EAAT2 was identified after N-deglycosylation. (PMID:20399272)
• This study demonitrated that Glutamate transporter variants reduce glutamate uptake in Alzheimer’s disease. (PMID:20416976)
• exon-skipping variants form heteromeric complexes with EAAT2wt or EAAT2b that traffic to the membrane but show reduced glutamate-dependent activity. This could allow glutamate to accumulate extracellularly and promote excitotoxicity. (PMID:20688910)
• riluzole increased the amount and activity of HSF1 to boost the expression of HSPs and GLT1 for neuroprotection under stress. (PMID:21098017)
• Results describe a homologous sequence within the 3’-UTR of the human and rat EAAT2/GLT-1 gene which is a partial sequence of the putative non-coding RNA, Ntab. (PMID:21110225)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc1a2a	ENSDARG00000052138
danio_rerio	slc1a2b	ENSDARG00000102453
mus_musculus	Slc1a2	ENSMUSG00000005089
rattus_norvegicus	Slc1a2	ENSRNOG00000005479

Paralogs (6): SLC1A3 (ENSG00000079215), SLC1A6 (ENSG00000105143), SLC1A5 (ENSG00000105281), SLC1A1 (ENSG00000106688), SLC1A4 (ENSG00000115902), SLC1A7 (ENSG00000162383)

Protein

Protein identifiers

Excitatory amino acid transporter 2 — P43004 (reviewed: P43004)

Alternative names: Glutamate/aspartate transporter II, Sodium-dependent glutamate/aspartate transporter 2, Solute carrier family 1 member 2

All UniProt accessions (24): P43004, A0A163QEF0, A0A2R8Y4D1, A0A2R8Y4N0, A0A2R8Y4W1, A0A2R8Y5Y1, A0A2R8Y642, A0A2R8Y6B8, A0A2R8Y6J5, A0A2R8Y740, A0A2R8Y860, A0A2R8Y862, A0A2R8YCL7, A0A2R8YD46, A0A2R8YFE3, A0A2R8YG01, A0A2R8YH93, A0A2R8YHI4, A0A2U3TZS7, A0A2U3U0E3, A2A2U1, C9J9N5, H0YEB1, H0YEK4

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. Essential for the rapid removal of released glutamate from the synaptic cleft, and for terminating the postsynaptic action of glutamate.

Subunit / interactions. Homotrimer. Isoform 3 can oligomerize with isoform 1. Interacts with AJUBA.

Subcellular location. Cell membrane.

Post-translational modifications. Glycosylated. Palmitoylation at Cys-38 is not required for correct subcellular localization, but is important for glutamate uptake activity.

Disease relevance. Developmental and epileptic encephalopathy 41 (DEE41) [MIM:617105] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE41 inheritance is autosomal dominant. 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.

Similarity. Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A2 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P43004-1	1	yes
P43004-2	2
P43004-3	3, EEAT2b

RefSeq proteins (3): NP_001182657, NP_001239581, NP_004162* (*=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 (95 total): helix 23, sequence conflict 15, topological domain 11, modified residue 11, binding site 10, transmembrane region 8, sequence variant 3, turn 3, strand 3, intramembrane region 2, glycosylation site 2, splice variant 2, chain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9JVV	ELECTRON MICROSCOPY	2.82
7XR4	ELECTRON MICROSCOPY	3.4
7XR6	ELECTRON MICROSCOPY	3.4
9JVW	ELECTRON MICROSCOPY	3.41
7VR7	ELECTRON MICROSCOPY	3.49
7VR8	ELECTRON MICROSCOPY	3.58
9JVX	ELECTRON MICROSCOPY	3.97

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43004-F1	77.64	0.47

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): 362–364; 393; 395; 397; 401; 442–446; 475; 482; 482; 486

Post-translational modifications (12): 3, 21, 25, 506, 521, 532, 534, 539, 544, 560, 564, 38

Glycosylation sites (2): 206, 216

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-210455	Astrocytic Glutamate-Glutamine Uptake And Metabolism
R-HSA-210500	Glutamate Neurotransmitter Release Cycle
R-HSA-9958863	SLC-mediated transport of amino acids
R-HSA-425393

MSigDB gene sets: 491 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CARBOHYDRATE_TRANSPORT, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_COCAINE, GOBP_NEUROTRANSMITTER_UPTAKE, GOBP_RESPONSE_TO_ACID_CHEMICAL, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_ADULT_BEHAVIOR, GOZGIT_ESR1_TARGETS_DN, GOBP_GROWTH, GOCC_CELL_SURFACE, GOBP_NEUROTRANSMITTER_TRANSPORT

GO Biological Process (32): glutathione biosynthetic process (GO:0006750), monoatomic ion transport (GO:0006811), neurotransmitter transport (GO:0006836), chemical synaptic transmission (GO:0007268), visual behavior (GO:0007632), response to xenobiotic stimulus (GO:0009410), response to wounding (GO:0009611), L-glutamate transmembrane transport (GO:0015813), telencephalon development (GO:0021537), adult behavior (GO:0030534), multicellular organism growth (GO:0035264), response to amino acid (GO:0043200), positive regulation of D-glucose import across plasma membrane (GO:0046326), protein homotrimerization (GO:0070207), transepithelial transport (GO:0070633), L-aspartate transmembrane transport (GO:0070778), D-aspartate import across plasma membrane (GO:0070779), cellular response to cocaine (GO:0071314), L-glutamate import across plasma membrane (GO:0098712), neurotransmitter reuptake (GO:0098810), L-aspartate import across plasma membrane (GO:0140009), transport across blood-brain barrier (GO:0150104), amino acid transport (GO:0006865), nervous system development (GO:0007399), response to light stimulus (GO:0009416), neutral amino acid transport (GO:0015804), transmembrane transport (GO:0055085), monoatomic anion transmembrane transport (GO:0098656), import into cell (GO:0098657), L-alpha-amino acid transmembrane transport (GO:1902475), L-cysteine transmembrane transport (GO:1903712), carboxylic acid transmembrane transport (GO:1905039)

GO Molecular Function (10): L-glutamate transmembrane transporter activity (GO:0005313), high-affinity L-glutamate transmembrane transporter activity (GO:0005314), monoatomic anion transmembrane transporter activity (GO:0008509), neutral L-amino acid transmembrane transporter activity (GO:0015175), glutamate:sodium symporter activity (GO:0015501), L-cysteine transmembrane transporter activity (GO:0033229), metal ion binding (GO:0046872), protein binding (GO:0005515), L-amino acid transmembrane transporter activity (GO:0015179), symporter activity (GO:0015293)

GO Cellular Component (14): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), axolemma (GO:0030673), vesicle (GO:0031982), presynaptic membrane (GO:0042734), cell body (GO:0044297), neuron projection terminus (GO:0044306), membrane raft (GO:0045121), astrocyte projection (GO:0097449), membrane protein complex (GO:0098796), glutamatergic synapse (GO:0098978), axon (GO:0030424), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transport	3
L-alpha-amino acid transmembrane transport	3
behavior	2
amino acid import across plasma membrane	2
L-glutamate transmembrane transport	2
presynapse	2
L-amino acid transmembrane transporter activity	2
amino acid transmembrane transporter activity	2
membrane	2
neuron projection	2
glutathione metabolic process	1
nonribosomal peptide biosynthetic process	1
modified amino acid biosynthetic process	1
sulfur compound biosynthetic process	1
anterograde trans-synaptic signaling	1
response to light stimulus	1
response to chemical	1
response to stress	1
L-glutamate import	1
forebrain development	1
anatomical structure development	1
multicellular organismal process	1
developmental growth	1
response to acid chemical	1
positive regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
D-glucose import across plasma membrane	1
protein homooligomerization	1
protein trimerization	1
aspartate transmembrane transport	1
D-aspartate transmembrane transport	1
response to cocaine	1
cellular response to alkaloid	1
cellular response to oxygen-containing compound	1
neurotransmitter uptake	1
establishment of localization in cell	1
dicarboxylic acid transmembrane transporter activity	1
acidic amino acid transmembrane transporter activity	1
L-glutamate transmembrane transporter activity	1

Protein interactions and networks

STRING

3050 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC1A2	GFAP	P14136	850
SLC1A2	GLUL	P15104	817
SLC1A2	SNCA	P37840	805
SLC1A2	SLC17A7	Q9P2U7	802
SLC1A2	SLC17A6	Q9P2U8	754
SLC1A2	GRIN2A	Q12879	735
SLC1A2	SOD1	P00441	731
SLC1A2	PAMR1	Q6UXH9	729
SLC1A2	ALDH1L1	O75891	713
SLC1A2	KCNJ10	P78508	713
SLC1A2	TARDBP	Q13148	711
SLC1A2	SLC32A1	Q9H598	707
SLC1A2	SLC7A11	Q9UPY5	694
SLC1A2	DLG4	P78352	689
SLC1A2	GRIN2B	Q13224	686

IntAct

26 interactions, top by confidence:

A	B	Type	Score
SLC1A2		psi-mi:“MI:0915”(physical association)	0.560
HTT	SLC1A2	psi-mi:“MI:0915”(physical association)	0.560
MAPT	SLC1A2	psi-mi:“MI:0914”(association)	0.460
SLC1A2	MAPT	psi-mi:“MI:0914”(association)	0.460
APBB1	SSPOP	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
SLC1A2	UBXN8	psi-mi:“MI:0914”(association)	0.350
GRB2	SLC1A2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (108): SLC1A2 (Reconstituted Complex), MAPT (Affinity Capture-Western), SLC1A2 (Affinity Capture-Western), RPL17 (Co-fractionation), RPL23A (Co-fractionation), RPL32 (Co-fractionation), RPL38 (Co-fractionation), RPL5 (Co-fractionation), SLC1A2 (Co-fractionation), AJUBA (Two-hybrid), AJUBA (Reconstituted Complex), SLC1A2 (Affinity Capture-Western), SLC3A2 (Affinity Capture-Western), SLC1A2 (Affinity Capture-MS), ACOT8 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2KTI4, A0A0J9UR41, A2QHC2, A2QNG6, A2R0Z5, E9E1W3, E9EDR6, E9EE69, F1Q749, G2WY98, G2XEK6, G4MVT6, G4N1B2, H6C2T9, H6C4I7, I1S097, I1S0T9, O48538, P29070, P30583, P30588, P30601, P30602, P31596, P32481, P43004, P43006, P49283, P54267, P55011, P55012, P55013, P55014, P55015, P55016, P55017, P55018, P58421, P59158, Q12564

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
SLC1A2	“up-regulates quantity”	“glutamic acid”	relocalization
CAV1	“down-regulates activity”	SLC1A2	binding
NHLRC1	“up-regulates activity”	SLC1A2	ubiquitination
NEDD4L	“down-regulates quantity”	SLC1A2	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	7
Uncertain significance	213
Likely benign	220
Benign	61

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
254265	NM_004171.4(SLC1A2):c.244G>C (p.Gly82Arg)	Pathogenic
438736	NM_004171.4(SLC1A2):c.244G>A (p.Gly82Arg)	Pathogenic
1703501	NM_004171.4(SLC1A2):c.872G>A (p.Gly291Asp)	Likely pathogenic
1802628	NM_004171.4(SLC1A2):c.689T>C (p.Ile230Thr)	Likely pathogenic
1803073	NM_004171.4(SLC1A2):c.872G>T (p.Gly291Val)	Likely pathogenic
2504082	NM_004171.4(SLC1A2):c.827T>G (p.Ile276Ser)	Likely pathogenic
2504083	NM_004171.4(SLC1A2):c.746del (p.Phe249fs)	Likely pathogenic
2504085	NM_004171.4(SLC1A2):c.1625A>G (p.His542Arg)	Likely pathogenic
4537855	NM_004171.4(SLC1A2):c.266T>C (p.Leu89Pro)	Likely pathogenic

SpliceAI

2118 predictions. Top by Δscore:

Variant	Effect	Δscore
11:35265588:T:A	donor_gain	1.0000
11:35265589:C:A	donor_gain	1.0000
11:35280861:ACTTA:A	donor_loss	1.0000
11:35280863:T:TC	donor_loss	1.0000
11:35280865:A:AC	donor_gain	1.0000
11:35280865:ACAG:A	donor_gain	1.0000
11:35280866:C:CT	donor_gain	1.0000
11:35280866:CA:C	donor_gain	1.0000
11:35280866:CAG:C	donor_gain	1.0000
11:35280866:CAGC:C	donor_gain	1.0000
11:35280866:CAGCA:C	donor_gain	1.0000
11:35281000:GG:G	acceptor_gain	1.0000
11:35281002:C:CC	acceptor_gain	1.0000
11:35281004:A:C	acceptor_gain	1.0000
11:35286752:CTCA:C	donor_loss	1.0000
11:35286753:TCAC:T	donor_loss	1.0000
11:35286754:CA:C	donor_loss	1.0000
11:35286755:A:C	donor_loss	1.0000
11:35286947:CAGCA:C	acceptor_gain	1.0000
11:35286948:AGCA:A	acceptor_gain	1.0000
11:35286949:GCA:G	acceptor_gain	1.0000
11:35286950:CA:C	acceptor_gain	1.0000
11:35286950:CAC:C	acceptor_gain	1.0000
11:35286952:C:CC	acceptor_gain	1.0000
11:35286959:C:CT	acceptor_gain	1.0000
11:35286960:A:T	acceptor_gain	1.0000
11:35306068:GCCTA:G	donor_loss	1.0000
11:35306069:CCTA:C	donor_loss	1.0000
11:35306070:CTA:C	donor_loss	1.0000
11:35306071:TA:T	donor_loss	1.0000

AlphaMissense

3772 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:35265714:C:T	G489E	1.000
11:35265715:C:A	G489W	1.000
11:35265715:C:G	G489R	1.000
11:35265715:C:T	G489R	1.000
11:35265722:G:C	D486E	1.000
11:35265722:G:T	D486E	1.000
11:35265723:T:A	D486V	1.000
11:35265723:T:C	D486G	1.000
11:35265723:T:G	D486A	1.000
11:35265724:C:G	D486H	1.000
11:35265726:C:T	G485D	1.000
11:35265727:C:G	G485R	1.000
11:35265732:A:T	V483D	1.000
11:35265734:A:C	N482K	1.000
11:35265734:A:T	N482K	1.000
11:35265736:T:C	N482D	1.000
11:35265752:C:A	R476S	1.000
11:35265752:C:G	R476S	1.000
11:35265753:C:A	R476M	1.000
11:35265757:C:G	D475H	1.000
11:35280874:A:G	W472R	1.000
11:35280874:A:T	W472R	1.000
11:35280876:T:A	D471V	1.000
11:35280876:T:G	D471A	1.000
11:35280877:C:G	D471H	1.000
11:35280888:A:T	L467Q	1.000
11:35280912:A:G	L459P	1.000
11:35280921:G:T	A456D	1.000
11:35280922:C:G	A456P	1.000
11:35280927:A:G	L454P	1.000

dbSNP variants (sampled 300 via entrez): RS1000033512 (11:35296514 T>C), RS1000035413 (11:35301341 T>C), RS1000068909 (11:35260118 C>G), RS1000108232 (11:35375844 A>T), RS1000175265 (11:35277850 G>T), RS1000212207 (11:35322298 T>A), RS1000222478 (11:35272034 T>A,C), RS1000251718 (11:35370256 G>A), RS1000260889 (11:35403023 A>G), RS1000288736 (11:35278499 G>A), RS1000291181 (11:35278129 G>A), RS1000299669 (11:35319024 T>A), RS1000350205 (11:35313566 G>A), RS1000395295 (11:35358226 T>C), RS1000421839 (11:35337172 G>A,C)

Disease associations

OMIM: gene MIM:600300 | disease phenotypes: MIM:617105

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 41	Strong	Autosomal dominant
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 41	Definitive	AD

Mondo (2): developmental and epileptic encephalopathy, 41 (MONDO:0014916), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (0):

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000121	Nephrocalcinosis
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000684	Delayed eruption of teeth
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Reduced tendon reflexes
HP:0001336	Myoclonus

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001590_1	Essential tremor	1.000000e-07
GCST002183_7	Relative hand skill in reading disability	9.000000e-06
GCST002448_5	Plasma omega-6 polyunsaturated fatty acid levels (adrenic acid)	2.000000e-06
GCST003182_1	Staphylococcus aureus nasal carriage (persistent)	8.000000e-06
GCST004684_2	Psychosis proneness (revised physical anhedonia scale and revised social anhedonia scale)	5.000000e-06
GCST004785_41	Vitiligo	5.000000e-18
GCST007431_13	Lung function (FEV1/FVC)	2.000000e-12
GCST007847_109	Type 2 diabetes	7.000000e-09
GCST007932_23	Medication use (thyroid preparations)	8.000000e-19
GCST008513_21	Health literacy	7.000000e-07
GCST009198_4	Corpus callosum mid-anterior volume	7.000000e-06
GCST010571_52	Autoimmune thyroid disease	2.000000e-17
GCST90013445_50	Type 1 diabetes	2.000000e-10
GCST90013445_60	Type 1 diabetes	2.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0009902	handedness
EFO:0005680	omega-6 polyunsaturated fatty acid measurement
EFO:0007757	persistent Staphylococcus aureus carrier status
EFO:0008337	psychosis predisposition measurement
EFO:0004713	FEV/FVC ratio
EFO:0009933	Thyroid preparation use measurement
EFO:0010104	health literacy measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4973 (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

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3794087	SLC1A2		0.00	0
rs4354668	SLC1A2		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 (7 total), top 7:

Ligand	Action	Affinity	Parameter
(R)-AS-1	Positive	7.96	pEC50
[3H]ETB-TBOA	Binding	7.8	pKd
WAY-213613	Inhibition	7.1	pIC50
DL-TBOA	Inhibition	6.9	pKB
SYM2081	Inhibition	5.5	pKB
dihydrokainate	Inhibition	5.0	pKB
threo-3-methylglutamate	Inhibition	4.7	pKB

Binding affinities (BindingDB)

16 measured of 18 human assays (19 total across all organisms); most potent 16 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5178416	EC50	0.26 nM
CHEMBL5202745	EC50	0.8 nM
CHEMBL5207363	EC50	79 nM
3-[3-Methyl-4-(4-chlorophenyl)benzoylamino]alanine	KI	190 nM
(1R*,2R*,3S*,4R*,6R*)-2-Amino-6-phenethyl-bicyclo[2.2.1]-heptane-2,3-dicarboxylic Acid Trifluoroacetate	IC50	1400 nM
WAY-213394	KI	1970 nM
WAY-855	KI	2200 nM
WAY-865	KI	2570 nM
WAY-212922	KI	3430 nM
N-[4-(2-BROMO-4,5-DIFLUOROPHENOXY)PHENYL]-L-ASPARAGINE	KI	5000 nM
(1R*,2R*,3S*,4R*,6R*)-2-Amino-6-butyl-bicyclo[2.2.1]heptane-2,3-dicarboxylic Acid Trifluoroacetate	IC50	14000 nM
(1R*,2R*,3S*,4R*,6R*)-2-Amino-6-[2-(4-chloro-phenyl)-ethyl]-bicyclo[2.2.1]heptane-2,3-dicarboxylic Acid Trifluoroacetate	IC50	17000 nM
(1S*,2S*,3R*,4S*,5S*)-2-Amino-5-phenethyl-bicyclo[2.2.1]-heptane-2,3-dicarboxylic Acid	IC50	19000 nM
(1R*,2R*,3S*,4R*,6R*)-2-Amino-6-[2-(2-hydroxy-phenyl)-ethyl]-bicyclo[2.2.1]heptane-2,3-dicarboxylic Acid Trifluoroacetate	IC50	21000 nM
(1R*,2R*,3S*,4R*,6R*)-2-Amino-6-propyl-bicyclo[2.2.1]-heptane-2,3-dicarboxylic Acid Trifluoroacetate	IC50	25000 nM
(1R*,2R*,3S*,4R*,6S*)-2-Amino-6-vinyl-bicyclo-[2.2.1]heptane-2,3-dicarboxylic Acid Trifluoroacetate	IC50	130000 nM

ChEMBL bioactivities

177 potent at pChembl≥5 of 261 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.52	EC50	0.03	nM	CHEMBL5565019
10.39	EC50	0.041	nM	CHEMBL5564020
10.00	EC50	0.1	nM	CHEMBL5187206
9.59	EC50	0.26	nM	CHEMBL5178416
9.52	EC50	0.3	nM	CHEMBL5202745
9.40	EC50	0.4	nM	CHEMBL5571181
9.15	EC50	0.7	nM	CHEMBL1579165
9.10	EC50	0.8	nM	CHEMBL5202745
9.05	EC50	0.9	nM	CHEMBL5594077
9.05	EC50	0.89	nM	CHEMBL5565003
9.00	EC50	1	nM	CHEMBL5178416
9.00	EC50	1	nM	CHEMBL5563875
9.00	EC50	1	nM	CHEMBL5567160
9.00	EC50	1	nM	CHEMBL5571220
9.00	EC50	1	nM	CHEMBL5564905
8.92	EC50	1.2	nM	CHEMBL5593916
8.52	EC50	3	nM	CHEMBL5569996
8.42	EC50	3.8	nM	CHEMBL5181457
8.22	EC50	6	nM	CHEMBL5590998
8.21	EC50	6.1	nM	CHEMBL5571309
8.21	EC50	6.1	nM	CHEMBL5573416
8.00	IC50	10	nM	CHEMBL1257519
7.96	EC50	11	nM	CHEMBL5206486
7.82	EC50	15	nM	CHEMBL5583680
7.78	IC50	16.6	nM	CHEMBL4173045
7.77	IC50	17	nM	CHEMBL4173045
7.77	IC50	17	nM	CHEMBL1257519
7.75	IC50	18	nM	CHEMBL4176427
7.74	IC50	18.2	nM	CHEMBL4176427
7.70	EC50	20	nM	CHEMBL5187206
7.68	IC50	21	nM	CHEMBL5409124
7.64	EC50	23	nM	CHEMBL5573090
7.60	EC50	25	nM	CHEMBL5206486
7.46	EC50	35.1	nM	CHEMBL5208038
7.44	IC50	36	nM	CHEMBL4176482
7.40	IC50	39.81	nM	CHEMBL4176482
7.33	IC50	47	nM	CHEMBL4177507
7.33	IC50	46.77	nM	CHEMBL4177507
7.23	IC50	59	nM	CHEMBL5423219
7.22	IC50	60	nM	CHEMBL2113122
7.15	IC50	71	nM	CHEMBL1628669
7.15	IC50	70.79	nM	CHEMBL1628669
7.11	EC50	78.5	nM	CHEMBL5207363
7.10	IC50	80	nM	CHEMBL2113115
7.10	IC50	80	nM	CHEMBL1628669
7.08	IC50	84	nM	CHEMBL4162363
7.07	IC50	85.11	nM	CHEMBL4162363
7.00	IC50	100	nM	CHEMBL2113110
7.00	IC50	100	nM	CHEMBL2113112
7.00	IC50	100	nM	CHEMBL2113116

PubChem BioAssay actives

177 with measured affinity, of 614 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
3-[(S)-(4-cyclohexylpiperazin-1-yl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-6-methoxy-1H-quinolin-2-one	2105514: Positive allosteric modulation of EAAT2 (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-[(4-fluorophenyl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-4-methylpiperazine	2105514: Positive allosteric modulation of EAAT2 (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
(2R)-2-(2,5-dioxopyrrolidin-1-yl)-N-[(2-fluorophenyl)methyl]propanamide	1864043: Activation of human EAAT2 transfected in Glial cells assessed as glutamate uptake	ec50	0.0001	uM
3-[(4-cyclohexylpiperazin-1-yl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-6-methoxy-1H-quinolin-2-one	1875451: Activation of human EAAT2 overexpressed in MDCK cells assessed as glutamate reuptake incubated for 5 mins by LCMS assay	ec50	0.0003	uM
6-methoxy-3-[[1-(2-phenylethyl)tetrazol-5-yl]-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]methyl]-1H-quinolin-2-one	1875489: Activation of human EAAT2 expressed in rat Astrocytes assessed as glutamate uptake by ELISA	ec50	0.0003	uM
1-[(1-benzyltetrazol-5-yl)-pyridin-4-ylmethyl]-4-methylpiperazine	2105514: Positive allosteric modulation of EAAT2 (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	0.0004	uM
1-[(1-benzyltetrazol-5-yl)-pyridin-3-ylmethyl]-4-cyclohexylpiperazine	2105514: Positive allosteric modulation of EAAT2 (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	0.0007	uM
3-[(R)-(4-cyclohexylpiperazin-1-yl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-6-methoxy-1H-quinolin-2-one	2105514: Positive allosteric modulation of EAAT2 (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	0.0009	uM
1-[(6-fluoro-3-pyridinyl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-4-methylpiperazine	2105514: Positive allosteric modulation of EAAT2 (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	0.0009	uM
5-[(4-methylpiperazin-1-yl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-1H-pyridin-2-one	2105514: Positive allosteric modulation of EAAT2 (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	0.0010	uM
1-cyclohexyl-4-[[1-(2-phenylethyl)tetrazol-5-yl]-pyridin-3-ylmethyl]piperazine	2105514: Positive allosteric modulation of EAAT2 (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	0.0010	uM
1-[(1-benzyltetrazol-5-yl)-pyridin-3-ylmethyl]-4-methylpiperazine	2105514: Positive allosteric modulation of EAAT2 (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	0.0010	uM
1-methyl-4-[[1-(2-phenylethyl)tetrazol-5-yl]-pyridin-3-ylmethyl]piperazine	2105514: Positive allosteric modulation of EAAT2 (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	0.0010	uM
4-[(1-benzyltetrazol-5-yl)-(4-methylpiperazin-1-yl)methyl]benzonitrile	2105514: Positive allosteric modulation of EAAT2 (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	0.0012	uM
2-(4-cyanophenyl)-N-[2-(4-fluorophenyl)ethyl]-2-(4-methylpiperazin-1-yl)acetamide	2105514: Positive allosteric modulation of EAAT2 (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	0.0030	uM
N-(4-methoxyphenyl)-2-oxo-2-(4-phenylpiperazin-1-yl)acetamide	1875451: Activation of human EAAT2 overexpressed in MDCK cells assessed as glutamate reuptake incubated for 5 mins by LCMS assay	ec50	0.0038	uM
4-[(4-methylpiperazin-1-yl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]benzonitrile	2105514: Positive allosteric modulation of EAAT2 (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	0.0060	uM
N-benzyl-2-(4-cyanophenyl)-2-(4-methylpiperazin-1-yl)acetamide	2105514: Positive allosteric modulation of EAAT2 (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	0.0061	uM
4-[(4-methylpiperazin-1-yl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]phenol	2105514: Positive allosteric modulation of EAAT2 (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	0.0061	uM
(2S,3S)-2-amino-3-[[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]butanedioic acid	1356070: Inhibition of human EAAT2 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0100	uM
(2R)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide	1864037: Activation of human EAAT2 transfected in COS7 cells assessed as glutamate uptake	ec50	0.0110	uM
N-[2-(4-fluorophenyl)ethyl]-2-(4-methylpiperazin-1-yl)-2-pyridin-3-ylacetamide	2105514: Positive allosteric modulation of EAAT2 (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	0.0150	uM
(2S,3S)-2-amino-3-[[3-[[3-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]butanedioic acid	1356070: Inhibition of human EAAT2 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0166	uM
(2S,3S)-2-amino-3-[[3-[3-[4-(trifluoromethyl)phenyl]propanoylamino]phenyl]methoxy]butanedioic acid	1356070: Inhibition of human EAAT2 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0180	uM
(2S,3S)-2-amino-3-[[3-[(4-phenylbenzoyl)amino]phenyl]methoxy]butanedioic acid	2028648: Inhibition of human EAAT2 transfected in MDCK cells assessed as reduction in [14C]glutamate uptake	ic50	0.0210	uM
6-methoxy-3-[(4-methylpiperazin-1-yl)-[1-(2-phenylethyl)tetrazol-5-yl]methyl]-1H-quinolin-2-one	2105514: Positive allosteric modulation of EAAT2 (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	0.0230	uM
N’-(4-methoxyphenyl)-N-[2-(4-methylpiperazin-1-yl)-2-phenylethyl]oxamide	1875451: Activation of human EAAT2 overexpressed in MDCK cells assessed as glutamate reuptake incubated for 5 mins by LCMS assay	ec50	0.0351	uM
(2S,3S)-2-amino-4-[4-(2-bromo-4,5-difluorophenoxy)anilino]-4-oxo-3-phenylmethoxybutanoic acid	1356070: Inhibition of human EAAT2 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0360	uM
(2S,3S)-2-amino-4-(9H-fluoren-2-ylamino)-4-oxo-3-phenylmethoxybutanoic acid	1356070: Inhibition of human EAAT2 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0468	uM
(2S,3S)-2-amino-3-[[3-[(4-methoxybenzoyl)amino]phenyl]methoxy]butanedioic acid	2028657: Inhibition of human EAAT2 transfected in African green monkey COS-1 cells assessed as reduction in [14C]glutamate uptake	ic50	0.0590	uM
(2S)-2-amino-4-oxo-4-[4-[3-(trifluoromethyl)phenyl]anilino]butanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.0600	uM
(2S)-2-amino-4-[4-(2-bromo-4,5-difluorophenoxy)anilino]-4-oxobutanoic acid	1356070: Inhibition of human EAAT2 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0708	uM
3-[(4-cyclohexylpiperazin-1-yl)-[1-(pyridin-4-ylmethyl)tetrazol-5-yl]methyl]-6,7-dimethoxy-1H-quinolin-2-one	1875451: Activation of human EAAT2 overexpressed in MDCK cells assessed as glutamate reuptake incubated for 5 mins by LCMS assay	ec50	0.0785	uM
(2S)-2-amino-4-[(7-fluoro-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.0800	uM
(2S,3S)-2-amino-3-[[3-[[2-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]butanedioic acid	1356070: Inhibition of human EAAT2 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.0840	uM
(2S)-2-amino-4-[4-(2-methylphenyl)anilino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.1000	uM
(2S)-2-amino-4-oxo-4-[[7-(trifluoromethyl)-9H-fluoren-2-yl]amino]butanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.1000	uM
(2S)-2-amino-4-[4-(3,4-dichlorophenyl)-3-methylanilino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.1000	uM
(2S)-2-amino-4-[(7-chloro-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.1000	uM
(2S)-2-amino-4-[3-methyl-4-[3-(trifluoromethyl)phenyl]anilino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.1000	uM
(2S,3S)-2-amino-3-[[3-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]phenyl]methoxy]butanedioic acid	1356070: Inhibition of human EAAT2 expressed in HEK293 cells assessed as reduction in [3H]-D-Asp uptake incubated for 4 mins by scintillation counting method	ic50	0.1071	uM
(2S)-2-amino-4-[4-(3,4-difluorophenoxy)anilino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.1300	uM
2-amino-4-(2-methyl-4-phenylanilino)-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.2000	uM
(2S)-2-amino-4-[4-(4-chlorophenyl)-3-methylanilino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.2000	uM
(2S)-2-amino-4-[4-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)anilino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.2000	uM
(2S)-2-amino-4-[(7-bromo-9H-fluoren-2-yl)amino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.2000	uM
(2S,3S)-2-amino-3-[[1-(4-methylphenyl)sulfonyl-3-thiophen-3-ylindol-6-yl]methoxy]butanedioic acid;2,2,2-trifluoroacetic acid	1725866: Inhibition of human EAAT2 transfected in HEK293 cells assessed as inhibition of [3H]-D-aspartate uptake incubated for 4 mins by TopCount scintillation counting analysis	ic50	0.2089	uM
2-amino-4-[(10-ethylphenoxazin-2-yl)amino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.3000	uM
(2S)-2-amino-4-[3-methyl-4-[4-(trifluoromethyl)phenyl]anilino]-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.3000	uM
(2S)-2-amino-4-(4-naphthalen-2-ylanilino)-4-oxobutanoic acid	255073: Inhibitory concentration against glutamate uptake in HEK cells expressing human Excitatory amino acid transporter 2	ic50	0.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases reaction, affects binding, increases reaction, decreases methylation (+1 more)	7
Tetrachlorodibenzodioxin	affects expression, decreases expression, increases expression	5
manganese chloride	increases abundance, affects binding, increases reaction, decreases expression, decreases reaction	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
bisphenol A	affects methylation, affects cotreatment, increases methylation, decreases expression	2
trichostatin A	decreases expression, increases expression	2
mercuric bromide	affects cotreatment, decreases expression	2
Estradiol	decreases expression	2
Manganese	decreases expression, decreases reaction, increases abundance, affects binding, increases reaction	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
IkK-16 compound	decreases expression, decreases reaction, increases abundance	1
perfluorodecanesulfonic acid	increases expression	1
TL8-506	affects cotreatment, increases expression	1
tungsten carbide	affects cotreatment, decreases expression	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
cinnamaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
pentanal	increases expression	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1

ChEMBL screening assays

90 unique, capped per target: 84 binding, 6 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1016588	Binding	Inhibition of glutamate-induced depolarization in human EAAT2 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
CHEMBL680704	Functional	Potency (100 uM) to induce a transport current in the absence of glutamate in oocytes expressing human excitatory amino acid transporter 2 (EAAT2)	Syntheses of optically pure beta-hydroxyaspartate derivatives as glutamate transporter blockers. — Bioorg Med Chem Lett

Cellosaurus cell lines

11 cell lines: 10 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0076	SNU-16	Cancer cell line	Female
CVCL_1708	SNU-C1	Cancer cell line	Male
CVCL_C9DM	SNU-16/Cas9-hyg	Cancer cell line	Female
CVCL_C9G9	SNU-C1/Cas9-hyg	Cancer cell line	Male
CVCL_D4DV	HEK-SLC1A2-KO-c4	Transformed cell line	Female
CVCL_E8SI	SNU-16 CDH17 KO clone 1C1	Cancer cell line	Female
CVCL_E8SJ	SNU-16 CDH17 KO clone 2A1	Cancer cell line	Female
CVCL_E8SK	SNU-16 human PDL1	Cancer cell line	Female
CVCL_L043	SNU-16-DOX	Cancer cell line	Female
CVCL_WY37	SNU-16Ad	Cancer cell line	Female

Clinical trials (associated diseases)

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