SLC1A6

Summary

SLC1A6 (solute carrier family 1 member 6, HGNC:10944) is a protein-coding gene on chromosome 19p13.12, encoding Excitatory amino acid transporter 4 (P48664). Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate.

Enables L-aspartate transmembrane transporter activity; L-glutamate transmembrane transporter activity; and glutamate:sodium symporter activity. Involved in L-aspartate import across plasma membrane; L-glutamate import across plasma membrane; and neurotransmitter uptake. Located in intermediate filament cytoskeleton and plasma membrane.

Source: NCBI Gene 6511 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 53 total
• MANE Select transcript: NM_005071

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10944
Approved symbol	SLC1A6
Name	solute carrier family 1 member 6
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Aliases	EAAT4
Ensembl gene	ENSG00000105143
Ensembl biotype	protein_coding
OMIM	600637
Entrez	6511

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 16 protein_coding, 1 retained_intron

ENST00000221742, ENST00000430939, ENST00000544886, ENST00000594383, ENST00000595863, ENST00000596697, ENST00000597262, ENST00000598504, ENST00000599636, ENST00000600144, ENST00000601761, ENST00000885391, ENST00000921261, ENST00000921262, ENST00000921263, ENST00000921264, ENST00000921265

RefSeq mRNA: 6 — MANE Select: NM_005071 NM_001272087, NM_001272088, NM_001384669, NM_001384670, NM_001384671, NM_005071

CCDS: CCDS12321, CCDS62578

Canonical transcript exons

ENST00000594383 — 10 exons

Exon	Start	End
ENSE00000689560	14964319	14964361
ENSE00000689562	14956476	14956709
ENSE00001632584	14952928	14953062
ENSE00001675755	14954135	14954329
ENSE00002205306	14962002	14962345
ENSE00003062660	14979309	14979864
ENSE00003467418	14971737	14971874
ENSE00003469042	14968303	14968507
ENSE00003493206	14972706	14972917
ENSE00003920796	14950033	14950390

Expression profiles

Bgee: expression breadth ubiquitous, 124 present calls, max score 95.47.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9039 / max 190.1358, expressed in 271 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179691	0.7886	198
179693	0.6136	224
179692	0.4171	186
179689	0.0552	29
179690	0.0294	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	95.47	gold quality
cerebellar cortex	UBERON:0002129	93.59	gold quality
cerebellar hemisphere	UBERON:0002245	93.58	gold quality
cerebellum	UBERON:0002037	93.24	gold quality
cortical plate	UBERON:0005343	93.03	gold quality
endothelial cell	CL:0000115	88.16	gold quality
left testis	UBERON:0004533	87.77	gold quality
right testis	UBERON:0004534	87.07	gold quality
paraflocculus	UBERON:0005351	85.89	gold quality
upper leg skin	UBERON:0004262	85.43	gold quality
testis	UBERON:0000473	85.34	gold quality
cerebellar vermis	UBERON:0004720	84.82	gold quality
nucleus accumbens	UBERON:0001882	84.29	gold quality
oocyte	CL:0000023	83.61	silver quality
caudate nucleus	UBERON:0001873	82.08	gold quality
prefrontal cortex	UBERON:0000451	81.81	gold quality
putamen	UBERON:0001874	81.08	gold quality
adult organism	UBERON:0007023	80.08	gold quality
sperm	CL:0000019	80.06	gold quality
cingulate cortex	UBERON:0003027	79.79	gold quality
anterior cingulate cortex	UBERON:0009835	79.60	gold quality
male germ cell	CL:0000015	79.36	gold quality
neocortex	UBERON:0001950	79.34	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	79.31	gold quality
frontal cortex	UBERON:0001870	79.20	gold quality
Brodmann (1909) area 46	UBERON:0006483	78.61	silver quality
right frontal lobe	UBERON:0002810	78.55	gold quality
telencephalon	UBERON:0001893	78.54	gold quality
cerebral cortex	UBERON:0000956	78.45	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.44	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.88
E-MTAB-4850	no	36.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RORA

miRNA regulators (miRDB)

11 targeting SLC1A6, 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-1252-3P	99.55	67.71	2862
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-1470	98.11	63.53	399
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-597-5P	96.82	67.57	732

Literature-anchored findings (GeneRIF, showing 8)

• At least one susceptibility locus for schizophrenia may be located within or nearby SLC1A6. (PMID:17221839)
• Independent, rather than cooperative anion conductance gating significantly alters predictions of the influence that EAAT4-mediated anion currents will have on synaptic transmission at low glutamate concentrations. (PMID:17360917)
• conclusion, maximal glutamate transport modulation by SGK1 is accomplished by direct EAAT4 stimulation and to a lesser extent by inhibition of intrinsic Nedd4-2. (PMID:17442044)
• a conserved aspartate determines pore properties of anion channels associated with excitatory amino acid transporter 4 (EAAT4) (PMID:20519505)
• strate-dependent gating of anion channels associated with excitatory amino acid transporter 4. (PMID:21572047)
• A twofold difference in functional EAAT4 levels is sufficient to alter signaling to Bergman glia in reporter mice. (PMID:22302796)
• Decreased SLC1A6 expression in neuregulin 1 risk variant may be an adaptive effect to restore glutamate signalling in schizophrenia patients. (PMID:22424243)
• Lithium-sensitive GSK3ss is a powerful regulator of excitatory amino acid transporters EAAT3 and EAAT4. (PMID:27978527)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc1a6	ENSDARG00000010096
mus_musculus	Slc1a6	ENSMUSG00000005357
rattus_norvegicus	Slc1a6	ENSRNOG00000007509

Paralogs (6): SLC1A3 (ENSG00000079215), SLC1A5 (ENSG00000105281), SLC1A1 (ENSG00000106688), SLC1A2 (ENSG00000110436), SLC1A4 (ENSG00000115902), SLC1A7 (ENSG00000162383)

Protein

Protein identifiers

Excitatory amino acid transporter 4 — P48664 (reviewed: P48664)

Alternative names: Sodium-dependent glutamate/aspartate transporter, Solute carrier family 1 member 6

All UniProt accessions (8): E7EV13, P48664, M0QY32, M0R063, M0R0B5, M0R106, M0R1V3, M0R2V7

UniProt curated annotations — full annotation on UniProt →

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

Subunit / interactions. Homotrimer.

Subcellular location. Cell membrane.

Tissue specificity. Brain, mainly in the cerebellum. Expressed densely and selectively in cell bodies of Purkinje cells.

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. SLC1A6 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P48664-1	1	yes
P48664-2	2

RefSeq proteins (6): NP_001259016, NP_001259017, NP_001371598, NP_001371599, NP_001371600, NP_005062* (*=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 (27 total): binding site 10, transmembrane region 8, glycosylation site 3, intramembrane region 2, chain 1, topological domain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48664-F1	80.35	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): 388–390; 419; 421; 423; 427; 468–472; 501; 508; 508; 512

Post-translational modifications (1): 2

Glycosylation sites (3): 216, 232, 239

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-210500	Glutamate Neurotransmitter Release Cycle
R-HSA-9958863	SLC-mediated transport of amino acids
R-HSA-425393

MSigDB gene sets: 0 (showing top):

GO Biological Process (15): neurotransmitter uptake (GO:0001504), monoatomic ion transport (GO:0006811), neurotransmitter transport (GO:0006836), chemical synaptic transmission (GO:0007268), aspartate transmembrane transport (GO:0015810), L-glutamate transmembrane transport (GO:0015813), regulation of membrane potential (GO:0042391), establishment of localization in cell (GO:0051649), L-glutamate import across plasma membrane (GO:0098712), L-aspartate import across plasma membrane (GO:0140009), amino acid transport (GO:0006865), neutral amino acid transport (GO:0015804), transmembrane transport (GO:0055085), import into cell (GO:0098657), L-alpha-amino acid transmembrane transport (GO:1902475)

GO Molecular Function (8): L-glutamate transmembrane transporter activity (GO:0005313), high-affinity L-glutamate transmembrane transporter activity (GO:0005314), neutral L-amino acid transmembrane transporter activity (GO:0015175), L-aspartate transmembrane transporter activity (GO:0015183), glutamate:sodium symporter activity (GO:0015501), metal ion binding (GO:0046872), L-amino acid transmembrane transporter activity (GO:0015179), symporter activity (GO:0015293)

GO Cellular Component (7): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020), presynaptic membrane (GO:0042734), intermediate filament cytoskeleton (GO:0045111), membrane protein complex (GO:0098796), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Neurotransmitter release cycle	1
SLC-mediated transmembrane transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	5
amino acid transmembrane transport	2
carboxylic acid transmembrane transport	2
L-alpha-amino acid transmembrane transport	2
L-glutamate transmembrane transport	2
amino acid import across plasma membrane	2
L-aspartate transmembrane transport	2
acidic amino acid transmembrane transporter activity	2
L-amino acid transmembrane transporter activity	2
amino acid transmembrane transporter activity	2
membrane	2
neurotransmitter transport	1
import into cell	1
anterograde trans-synaptic signaling	1
C4-dicarboxylate transport	1
acidic amino acid transport	1
nitrogen compound transport	1
L-glutamate import	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
establishment of localization	1
cellular localization	1
amino acid transport	1
cellular process	1
L-amino acid transport	1
dicarboxylic acid transmembrane transporter activity	1
L-glutamate transmembrane transporter activity	1
glutamate:sodium symporter activity	1
neutral amino acid transport	1
C4-dicarboxylate transmembrane transporter activity	1
amino acid:sodium symporter activity	1
sodium:dicarboxylate symporter activity	1
cation binding	1
carboxylic acid transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1394 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC1A6	SPTBN2	O15020	949
SLC1A6	ARHGEF11	O15085	914
SLC1A6	GRID2	O43424	700
SLC1A6	SPTB	P11277	633
SLC1A6	SPTBN1	Q01082	578
SLC1A6	MCHR1	Q99705	577
SLC1A6	SLC3A2	P08195	514
SLC1A6	MAP1A	P78559	511
SLC1A6	SLC38A2	Q96QD8	507
SLC1A6	MAP1S	Q66K74	497
SLC1A6	GLUL	P15104	495
SLC1A6	LPAR1	P78351	493
SLC1A6	RGS17	Q9UGC6	490
SLC1A6	SLC7A6	Q92536	490
SLC1A6	SLC17A7	Q9P2U7	488

IntAct

3 interactions, top by confidence:

A	B	Type	Score
SLC1A6	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC1A6	ARIH2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (56): SLC1A6 (Two-hybrid), SLC1A6 (Affinity Capture-RNA), SLC1A6 (Affinity Capture-MS), ABCA3 (Affinity Capture-MS), ADCK2 (Affinity Capture-MS), ADCY3 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), BAG4 (Affinity Capture-MS), BAG5 (Affinity Capture-MS), BAG6 (Affinity Capture-MS), BMPR1A (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), CSGALNACT2 (Affinity Capture-MS), CUX1 (Affinity Capture-MS), C17orf62 (Affinity Capture-MS)

ESM2 similar proteins: A0A6P3HVI0, A2VDL4, A4IHB9, D3ZJ25, E7EXX2, O00341, O19105, O35544, O35874, O35921, O43511, O54902, O57321, P24942, P31596, P31597, P43003, P43004, P43005, P43006, P43007, P46411, P48664, P49281, P49282, P51906, P51907, P51912, P55012, P56564, Q10901, Q15758, Q25605, Q4R8W8, Q5BKR2, Q5R6B8, Q5R839, Q86UD5, Q8BJA2, Q8IVJ1

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

3 interactions.

A	Effect	B	Mechanism
SLC1A6	“up-regulates quantity”	“glutamic acid”	relocalization
CAV1	“down-regulates activity”	SLC1A6	binding
RORA	“up-regulates quantity by expression”	SLC1A6	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1866 predictions. Top by Δscore:

Variant	Effect	Δscore
19:14950389:CA:C	acceptor_gain	1.0000
19:14950390:ACT:A	acceptor_loss	1.0000
19:14950391:C:CC	acceptor_gain	1.0000
19:14950391:CTGGT:C	acceptor_loss	1.0000
19:14950394:G:C	acceptor_gain	1.0000
19:14950394:G:GC	acceptor_gain	1.0000
19:14950397:C:CT	acceptor_gain	1.0000
19:14950398:A:T	acceptor_gain	1.0000
19:14952923:CTCA:C	donor_loss	1.0000
19:14952924:TCACA:T	donor_loss	1.0000
19:14952925:CA:C	donor_loss	1.0000
19:14952926:A:AC	donor_gain	1.0000
19:14952927:C:CA	donor_gain	1.0000
19:14953058:TGATG:T	acceptor_gain	1.0000
19:14953059:GATG:G	acceptor_gain	1.0000
19:14953060:ATG:A	acceptor_gain	1.0000
19:14953061:TG:T	acceptor_gain	1.0000
19:14953063:C:CC	acceptor_gain	1.0000
19:14954131:TCA:T	donor_loss	1.0000
19:14954132:CAC:C	donor_loss	1.0000
19:14954133:A:AG	donor_loss	1.0000
19:14954134:CCTGA:C	donor_loss	1.0000
19:14954325:CCGAG:C	acceptor_gain	1.0000
19:14954326:CGAG:C	acceptor_gain	1.0000
19:14954326:CGAGC:C	acceptor_gain	1.0000
19:14954328:AG:A	acceptor_gain	1.0000
19:14954330:C:CC	acceptor_gain	1.0000
19:14956470:CCATA:C	donor_loss	1.0000
19:14956472:ATACC:A	donor_loss	1.0000
19:14956473:TA:T	donor_loss	1.0000

AlphaMissense

212 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:14972884:G:C	F9L	0.861
19:14972884:G:T	F9L	0.861
19:14972886:A:G	F9L	0.861
19:14972885:A:C	F9C	0.701
19:14972885:A:G	F9S	0.634

dbSNP variants (sampled 300 via entrez): RS1000026166 (19:14982734 T>C), RS1000054697 (19:14973470 G>A,C), RS1000162155 (19:14995966 GA>G), RS1000168165 (19:14996374 T>C), RS1000213373 (19:14996334 G>A), RS1000224054 (19:15000814 A>G), RS1000234616 (19:14966432 C>A,T), RS1000255530 (19:14999286 T>G), RS1000257943 (19:14957372 T>A), RS1000312614 (19:14951220 C>A,T), RS1000343859 (19:14951572 A>G), RS1000367873 (19:14979349 G>A), RS1000371899 (19:14999538 C>T), RS1000418170 (19:14990888 G>T), RS1000432972 (19:14960563 A>C)

Disease associations

OMIM: gene MIM:600637 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006088_56	Familial squamous cell lung carcinoma	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006953	family history of lung cancer

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Glutamate transporter subfamily

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

Ligand	Action	Affinity	Parameter
[3H]ETB-TBOA	Binding	7.9	pKd
DL-TBOA	Inhibition	5.4	pKi
threo-3-methylglutamate	Inhibition	4.3	pKi

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	5
trichostatin A	affects cotreatment, decreases expression	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	affects expression, decreases expression	2
3,4-dichloroaniline	decreases expression	1
sodium arsenite	increases expression	1
tamibarotene	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcitriol	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Diuron	increases expression	1
Indomethacin	increases expression	1
Lead	affects expression	1
Plant Oils	decreases expression	1
Potassium Dichromate	increases expression	1
Fatty Acids, Omega-3	increases expression	1
Lactic Acid	increases expression	1
Acrylamide	decreases expression	1
Fatty Acids, Omega-6	decreases expression	1

Clinical trials (associated diseases)

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