Affinage

SLC1A3

Excitatory amino acid transporter 1 · UniProt P43003

Length
542 aa
Mass
59.6 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC1A3 (EAAT1/GLAST) is a Na+-coupled high-affinity glutamate/aspartate transporter that clears synaptic glutamate in astrocytes and Bergmann glia, sustaining normal Purkinje cell firing and protecting neurons from excitotoxicity (PMID:29741614, PMID:16647773). Transport requires a defined ion-coupling cycle, and a migraine-associated T387P mutation selectively abolishes the K+-bound retranslocation step while preserving Na+-dependent anion currents, defining impaired K+ binding as a discrete transport defect (PMID:29066757). Surface abundance and activity are set by an extensive regulatory network: substrate-driven, actin-dependent trafficking to the plasma membrane (PMID:10575016); CaMKII phosphorylation of N-terminal T26/T37 (PMID:27889915); SGK1/SGK3/PKB-antagonized, Nedd4-2-dependent ubiquitination acting through residue T482 (PMID:12911626); PKC-mediated modification of cytoplasmic epitopes (PMID:15569258); and GSK3β-mediated phosphorylation that suppresses GLAST while stimulating GLT-1 (PMID:25454285). Transcription is bidirectionally controlled at a TATA-less core promoter, positively by NF-κB acting with Sp1/Sp3 and USF1 and negatively by YY1 with HDAC co-repressors, integrating glutamate, cytokine, and growth-factor signals (PMID:26269591, PMID:14713304). Beyond transport, GLAST activity orchestrates downstream membrane and signaling events—directing FXYD2 to the surface to modulate Na+,K+-ATPase (PMID:17316900) and triggering Ca2+/PI3K/PKB/mTOR-AP-1 signaling in glia (PMID:21856347)—and is co-opted in cancer, where p53 induces SLC1A3 to fuel aspartate/glutamate-dependent TCA cycle and biosynthetic metabolism under nutrient stress (PMID:30122553, PMID:31523835). SLC1A3 also coordinates epithelial stem/progenitor activation across skin niches upstream of mGluR5 (PMID:29615452). Loss-of-function, dominant-negative, and gain-of-function missense mutations in SLC1A3 cause episodic ataxia type 6 through partial transport, trafficking, or expression defects to which the cerebellum is acutely sensitive (PMID:16116111, PMID:19139306, PMID:32741053).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1996 Medium

    Establishing the genomic and promoter architecture of Slc1a3 framed how transcription of the transporter could be controlled.

    Evidence Genomic library screening, promoter-luciferase reporters and chromosomal mapping in COS-1 cells

    PMID:8661010

    Open questions at the time
    • Did not identify the trans-acting factors binding the CCAAT/GC boxes
    • Mouse promoter only; human core element unresolved at this stage
  2. 1996 Medium

    Linking glutamate exposure to up-regulation of GLAST protein showed the transporter is dynamically tuned to substrate load via kainate-type receptor signaling.

    Evidence Primary astrocyte uptake assays, Western blot and pharmacological receptor antagonists

    PMID:9051792

    Open questions at the time
    • Distinguished post-transcriptional regulation but did not define the molecular trafficking step
    • Receptor coupling to transporter expression left at the pharmacological level
  3. 1999 High

    Demonstrating that substrate transport itself drives rapid actin-dependent surface delivery of GLAST established a feed-forward mechanism for matching uptake capacity to glutamate availability.

    Evidence Astrocyte biotinylation, uptake assays and actin-disruption pharmacology

    PMID:10575016

    Open questions at the time
    • Trafficking machinery/adaptors mediating surface delivery not identified
    • Whether this acute mechanism applies in vivo untested
  4. 2003 Medium

    Identifying the human EAAT1 core promoter and its Sp1/Sp3 and USF1 factors, and the SGK/PKB-Nedd4-2-T482 ubiquitination axis, defined parallel transcriptional and post-translational set-points for transporter abundance.

    Evidence Promoter deletion/EMSA in human astrocytes; Xenopus oocyte electrophysiology with Nedd4-2/SGK/PKB co-expression and T482 mutagenesis

    PMID:12911626 PMID:14713304

    Open questions at the time
    • Whether T482 is directly phosphorylated by SGK/PKB not shown
    • Promoter factor interactions not tested in vivo
  5. 2003 Medium

    Showing glutamate represses GLAST transcription through Ca2+-permeable AMPA receptors, PKC and c-Jun revealed a negative arm balancing substrate-induced up-regulation.

    Evidence Bergmann glia promoter-reporter, uptake and RT-PCR with AMPA/PKC inhibitors

    PMID:12824049

    Open questions at the time
    • Direct promoter element for c-Jun not mapped here
    • Reconciliation with substrate-induced up-regulation not addressed
  6. 2004 High

    Distinguishing PKC-induced epitope modification from protein loss clarified that acute PKC signaling modifies cytoplasmic regions of GLAST rather than degrading it.

    Evidence Astrocyte transport assays, surface biotinylation and flag-tagged GLAST with PKC inhibitor

    PMID:15569258

    Open questions at the time
    • Specific modified residues not identified
    • Functional consequence of epitope modification beyond a modest activity change unclear
  7. 2005 High

    The first disease mutation showed EAAT1 loss-of-function and a paralog-specific dominant-negative effect, indicating selective EAAT1-EAAT1 multimerization underlies dominant inheritance.

    Evidence Heterologous expression, uptake assays and co-expression dominant-negative tests

    PMID:16116111

    Open questions at the time
    • Structural basis of selective multimerization not resolved
    • In vivo neuronal consequence not modeled
  8. 2006 High

    Genetic deletion in mice placed GLAST upstream of NMDA receptor overactivation in cerebellar circuits and demonstrated its protective role against excitotoxic Purkinje cell loss.

    Evidence GLAST and EAAT4 knockout mice with in vivo electrophysiology, NMDA blockade epistasis and ischemia histology

    PMID:16647773 PMID:29741614

    Open questions at the time
    • Cell-autonomous vs. circuit-level contributions not fully separated
    • Mechanism of EAAT4 cooperativity unresolved
  9. 2007 Medium

    Discovering that GLAST activity directs FXYD2 and ASCT2 surface trafficking, and that GDNF/neurturin up-regulate GLAST via PI3K/Src, expanded its role from transporter to organizer of downstream membrane transport and neuroprotection.

    Evidence Human fetal astrocyte biotinylation with FXYD2/GS siRNA and transporter block; rat retina with PI3K/Src inhibitors, GLAST siRNA and RGC survival

    PMID:16516348 PMID:17316900 PMID:18064044

    Open questions at the time
    • Molecular link coupling GLAST transport to FXYD2/ASCT2 trafficking unknown
    • Glutamine-sensing mechanism for ASCT2 induction not defined
  10. 2007 Medium

    YY1 was identified as the transcription factor mediating glutamate-induced GLAST repression, providing the trans-acting basis for the negative regulatory arm.

    Evidence Bergmann glia promoter-reporter with YY1 site mutation, uptake, RT-PCR and EMSA

    PMID:17394550

    Open questions at the time
    • Co-repressor partners not yet defined in this study
    • Signaling link from glutamate to YY1 binding incomplete
  11. 2010 High

    Defining the P2X7R-driven Ca2+/PI3K-PLCγ-CaMKII-PKC cascade that destabilizes GLAST mRNA, and the ASK1-dependent stress pathway downstream of GLAST loss, connected extracellular ATP and oxidative/TNF stress to transporter levels and neuronal survival.

    Evidence Astrocyte P2X7R knockdown, promoter and RNA-decay assays; GLAST/ASK1 double-knockout glaucoma model

    PMID:20070863 PMID:20489729

    Open questions at the time
    • cis-element conferring mRNA instability not mapped
    • ASK1 pathway placement is epistatic, not biochemically direct on GLAST
  12. 2010 High

    The Drosophila ortholog established Eaat1 as essential for glutamate homeostasis in locomotor circuits and revealed Fringe/Delta-Notch control of its glial expression developmentally.

    Evidence Fly loss-of-function genetics, motor neuron electrophysiology, locomotion assays and Notch pathway epistasis

    PMID:20980602

    Open questions at the time
    • Conservation of Notch-driven regulation in mammals untested
    • Mapping to specific synaptic transmitter clearance steps incomplete
  13. 2011 Medium

    Showing transport-dependent activation of Ca2+/PI3K/PKB-mTOR-AP-1 signaling cast GLAST as a signaling node, not merely a transporter, in glia.

    Evidence Bergmann glia substrate treatments with mTOR phosphorylation, pathway inhibitors and AP-1 reporters

    PMID:21856347

    Open questions at the time
    • How transport flux couples to Ca2+/PI3K signaling mechanistically unknown
    • Downstream AP-1 target genes not identified
  14. 2014 Medium

    Demonstrating that GSK3β oppositely regulates GLAST and GLT-1 through differential phosphorylation revealed transporter-selective kinase control.

    Evidence COS-7/oocyte expression with activity, surface and 32Pi phosphorylation assays plus GSK3β inhibitors

    PMID:25454285

    Open questions at the time
    • GSK3β phosphosites on GLAST not mapped
    • Direct vs. indirect phosphorylation not distinguished
  15. 2015 High

    Integrating NF-κB as a positive and YY1/HDAC as a negative promoter regulator, with manganese and EGF inputs, unified the bidirectional transcriptional control of EAAT1.

    Evidence Human astrocyte promoter mutagenesis, YY1 siRNA, NF-κB inhibition, RT-qPCR and uptake assays

    PMID:26269591

    Open questions at the time
    • Cooperativity/competition between NF-κB and YY1 at the promoter not resolved
    • In vivo relevance of manganese-YY1 axis untested here
  16. 2017 High

    Identifying CaMKII phosphorylation of N-terminal T26/T37 as required for constitutive transport, and a migraine T387P mutation that abolishes K+-retranslocation, refined both the regulatory and ion-coupling mechanisms of EAAT1.

    Evidence HEK293T uptake with peptide arrays/GST binding and T37A mutagenesis; mammalian patch clamp with fast substrate application and surface biochemistry

    PMID:27889915 PMID:29066757

    Open questions at the time
    • Whether T37 phosphorylation regulates trafficking or intrinsic turnover unclear
    • Structural basis of K+ binding defect not solved
  17. 2018 High

    Linking p53-induced SLC1A3 to maintenance of TCA cycle flux and biosynthesis under glutamine deprivation, and an upstream role in mGluR5-coordinated skin stem-cell activation, extended its function into tumor metabolic adaptation and tissue regeneration.

    Evidence Isotope flux, xenograft growth with SLC1A3 knockdown/overexpression; mouse conditional knockout, fate-mapping and mGluR5 pharmacology

    PMID:29615452 PMID:30122553

    Open questions at the time
    • Direct p53 binding to the SLC1A3 locus inferred, not fully demonstrated
    • Mechanism coupling SLC1A3 transport to mGluR5 signaling undefined
  18. 2019 Medium

    Showing SLC1A3 drives aspartate/glutamate uptake supporting asparaginase resistance, and that its transport direction in glioblastoma stem cells depends on Na+/K+-ATPase, established context-dependent transporter directionality as a therapeutic vulnerability.

    Evidence Functional genetic screen with metabolic profiling and xenografts; GBM stem cells with Na+/K+-ATPase rescue and UCPH-101 inhibition in vivo

    PMID:30418668 PMID:31523835

    Open questions at the time
    • Tumor-type generality of the directionality switch unclear
    • Whether transport reversal is exploitable across cancers untested
  19. 2020 High

    Systematic comparison of EA6 mutations showed they produce graded transport, trafficking, and expression defects, explaining the cerebellum's sensitivity to even partial EAAT1 dysfunction.

    Evidence Heterologous expression with confocal imaging, Western blot and patch clamp across mutations

    PMID:32741053

    Open questions at the time
    • Genotype-phenotype severity mapping incomplete
    • In vivo modeling of individual variants lacking
  20. 2021 Medium

    Linking reduced EAAT1 function to prolonged Purkinje cell EPSCs and SCA1-like neurodegeneration cast transporter dysfunction as an active driver of cerebellar pathology.

    Evidence Bergmann glia optogenetics with Purkinje cell patch clamp and ataxin-1 knock-in comparison

    PMID:33753288

    Open questions at the time
    • Direct biochemical mechanism reducing EAAT1 function during optogenetic activation unresolved
    • Causal link to human SCA1 inferential

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse phosphorylation, ubiquitination, and trafficking inputs are integrated structurally on a single transporter, and how transport directionality is switched between clearance and release across tissues, remain unresolved.
  • No structural model integrating regulatory phosphosites
  • Mechanism determining net uptake vs. efflux in tumor vs. glia undefined
  • Direct kinase-substrate relationships for several modifications unproven

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140104 molecular carrier activity 2
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-1430728 Metabolism 2 R-HSA-382551 Transport of small molecules 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
CAMK2FXYD2GSK3BNEDD4-2PKBSGK1TP53

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 A heterozygous missense mutation in SLC1A3/EAAT1 causes markedly reduced glutamate uptake capacity. When co-expressed, the mutant EAAT1 specifically decreased wild-type EAAT1 activity (dominant-negative effect) but did not affect EAAT2 or EAAT3, indicating that mutant EAAT1 multimerizes specifically with wild-type EAAT1. Heterologous expression of mutant EAAT1, glutamate uptake assays, co-expression dominant-negative experiments Neurology High 16116111
2003 Surface expression and transport activity of EAAT1 are regulated by the ubiquitin ligase Nedd4-2 and serum/glucocorticoid-inducible kinases SGK1/SGK3 and protein kinase B (PKB). Nedd4-2 co-expression decreases EAAT1-mediated glutamate currents in Xenopus oocytes, an effect reversed by constitutively active SGK1, SGK3, or PKB. Site-directed mutagenesis identified phosphorylation site T482 in EAAT1 as important, with a phospho-mimetic T482D mutation increasing transport activity. Xenopus oocyte expression, electrophysiological recording of glutamate-induced currents, site-directed mutagenesis of EAAT1 and Nedd4-2 Journal of neurochemistry High 12911626
1999 Glutamate stimulates its own uptake in astrocytes by rapidly increasing GLAST/EAAT1 expression at the cell surface (increased Vmax). This effect requires transporter activity (not receptor activation), is mimicked by the non-metabolizable substrate D-aspartate, does not occur in Na+-free medium, and is blocked by actin-disrupting agents cytochalasin B and D, indicating actin cytoskeleton-dependent trafficking of GLAST to the plasma membrane. Primary astrocyte cultures, glutamate uptake assays, biotinylation labeling of cell-surface proteins, pharmacological inhibition of actin polymerization The Journal of neuroscience High 10575016
2004 Protein kinase C (PKC) activation by PMA acutely increases GLAST transport activity (~20%) in primary astrocytes but simultaneously reduces total and cell-surface GLAST immunoreactivity, indicating PKC modifies multiple intracellular epitopes of GLAST. Flag-tagged GLAST introduced by lentiviral vectors showed no change in flag immunoreactivity despite loss of GLAST antibody signal, demonstrating PKC causes post-translational modification of cytoplasmic epitopes rather than protein loss. Primary astrocyte cultures, phorbol ester treatment, glutamate transport assays, biotinylation of cell-surface proteins, lentiviral transduction of flag-tagged GLAST, PKC inhibitor bisindolylmaleimide II Journal of neurochemistry High 15569258
2017 CaMKII constitutively regulates EAAT1 glutamate transport activity. Pharmacological inhibition of CaMKII reduces EAAT1-mediated [3H]-glutamate uptake in HEK293T cells. SPOTS peptide array and GST-fusion protein binding identified phosphorylation sites T26 and T37 in EAAT1's N-terminus as CaMKII substrates; a non-phosphorylatable T37A mutation diminished EAAT1-mediated glutamate uptake, identifying CaMKII-mediated phosphorylation at T37 as important for constitutive EAAT1 function. HEK293T heterologous expression, [3H]-glutamate uptake assay, SPOTS peptide array, GST-fusion protein biochemistry, site-directed mutagenesis (T37A), dominant-negative CaMKII overexpression Journal of neurochemistry High 27889915
2009 A C186S missense mutation in EAAT1/SLC1A3 causes a modest but significant reduction in glutamate uptake. This mutation segregates with episodic ataxia in a family, and the severity of EA6 symptoms correlates with the degree of glutamate transporter dysfunction. Direct sequencing of SLC1A3, glutamate uptake assay in cells expressing mutant EAAT1 Archives of neurology Medium 19139306
2017 A T387P mutation in hEAAT1 identified in a migraine patient diminishes glutamate uptake rates and reduces EAAT1 surface membrane expression. Whole-cell patch clamp and fast substrate application showed that T387P specifically abolishes K+-bound retranslocation while preserving Na+-dependent anion currents, identifying impaired K+ binding as a novel mechanism of glutamate transport dysfunction. Heterologous expression in mammalian cells, whole-cell patch clamp, fast substrate application, Western blot/biochemical analysis of surface expression Scientific reports High 29066757
2020 Functional consequences of all known EA6-associated SLC1A3 mutations were compared: mutations cause a range of impairments including reduced transport function, impaired trafficking to the plasma membrane, and increased protein expression. Many mutations caused only slight individual changes, demonstrating that the cerebellum is highly sensitive to even partial EAAT1 dysfunction. Heterologous expression in mammalian cells, confocal imaging, Western blot, whole-cell patch clamp recording of transport and anion currents Human mutation High 32741053
2011 A missense variant E219D in SLC1A3 increases glutamate uptake 1.66-fold and increases surface membrane EAAT1 protein 1.5-fold in HEK293 cells, demonstrating a gain-of-function effect on transport activity. [3H]-glutamate uptake assay and biotin-mediated membrane protein pull-down in transfected HEK293 cells Psychiatric genetics Medium 21233784
2007 GLAST/EAAT1 activity directs FXYD2/gamma subunit of Na+,K+-ATPase to the astrocyte cell surface. When GLAST transport was blocked by TFB-TBOA, FXYD2 surface expression was reduced; siRNA knockdown of FXYD2 did not affect GLAST trafficking but abolished the glutamate uptake-dependent activation of Na+,K+-ATPase, demonstrating that GLAST activity drives FXYD2 trafficking which in turn modulates the sodium pump. Primary human fetal astrocyte cultures, glutamate uptake assays, biotinylation of surface proteins, siRNA knockdown of FXYD2, selective transporter inhibitor TFB-TBOA Neurochemistry international Medium 17316900
2006 GLAST/EAAT1 expression in astrocytes is required to sustain normal spontaneous simple spike activity in zebrin-negative Purkinje cells by restricting NMDA receptor activation. In GLAST knockout mice, NMDA receptor blockade restored spontaneous PC activity and alleviated motor deficits, placing GLAST upstream of NMDA receptor overactivation in the cerebellum. GLAST knockout mice, in vivo electrophysiology (spontaneous Purkinje cell firing), pharmacological NMDA receptor blockade, behavioral motor testing Human molecular genetics High 29741614
2006 GLAST knockout mice show selective loss of Purkinje cells with low EAAT4 expression after global brain ischemia, demonstrating that GLAST protects against excitotoxic cerebellar damage in concert with EAAT4. GLAST and EAAT4 knockout mice, cardiac arrest model, histological quantification of Purkinje cell loss Neuroscience research Medium 16647773
2010 In GLAST-deficient mice (a model of normal tension glaucoma), ASK1 deficiency protects retinal ganglion cells and improves visual function. TNF-induced activation of p38 MAPK and iNOS production were suppressed in ASK1-deficient Müller glia, and TNF-induced RGC death was suppressed in ASK1-deficient RGCs, placing ASK1 downstream of GLAST-loss-induced oxidative/TNF stress leading to RGC apoptosis. GLAST-/- and ASK1-/- double knockout mice, multifocal electroretinography, histology, biochemical analysis of glutathione and malondialdehyde, cell death assays in primary Müller cells and RGCs Cell death and differentiation Medium 20489729
1996 Long-term treatment of astrocytes with L-glutamate or kainate (but not AMPA or tACPD) causes up-regulation of GLAST protein and increased D-aspartate uptake. The effect of glutamate is blocked by the kainate/AMPA receptor antagonist CNQX, and is mimicked by dbcAMP, indicating GLAST expression is regulated post-transcriptionally through kainate-type glutamate receptor signaling. Primary astrocyte cultures, D-[3H]aspartate uptake assays, Western blot quantification of GLAST protein, pharmacological receptor antagonists Neuroreport Medium 9051792
2003 Glutamate down-regulates GLAST mRNA levels and promoter activity in Bergmann glia via Ca2+-permeable AMPA receptors, with involvement of protein kinase C and the transcription factor c-Jun. Primary chick cerebellar Bergmann glia cultures, [3H]-D-aspartate uptake, promoter-reporter assays, RT-PCR, pharmacological inhibitors of AMPA receptors/PKC Brain research. Molecular brain research Medium 12824049
2007 YY1 (Ying-Yang 1) transcription factor mediates glutamate-induced transcriptional repression of GLAST/EAAT1. Glutamate increases YY1 DNA binding; overexpression of YY1 reduces GLAST uptake, mRNA levels, and chglast promoter activity; a YY1 binding site in the GLAST promoter is required for the glutamate-dependent repression. Cultured chick cerebellar Bergmann glia, promoter-reporter assay with YY1 site mutations, [3H]-D-aspartate uptake, RT-PCR, EMSA for YY1 binding Journal of neurochemistry Medium 17394550
2015 NF-κB is a positive transcriptional regulator of EAAT1/GLAST; mutation of NF-κB binding sites in the EAAT1 promoter decreases activity, and NF-κB inhibition reduces EAAT1 mRNA/protein levels and glutamate uptake. YY1 acts as a critical negative regulator, with HDAC co-repressors; manganese decreases EAAT1 expression via YY1, and HDAC inhibition reverses this. EGF increases EAAT1 expression via NF-κB. Human astrocyte H4 cells, promoter-reporter assays with NF-κB and YY1 site mutations, siRNA knockdown of YY1, NF-κB inhibition, RT-qPCR, Western blot, glutamate uptake assay The Journal of biological chemistry High 26269591
2003 The human EAAT1 promoter core element (−57 to +20 bp) is TATA-box-less and depends on a GC-box at −52/−39 bound by Sp1/Sp3 and an E-box near the TSS bound by USF1. cAMP and EGF increase EAAT1 promoter activity and mRNA/glutamate uptake in human astrocytes; TNF-α reduces both promoter activity and EAAT1 mRNA expression. Cloning and transfection of human EAAT1 promoter deletion constructs, EMSA, supershift and competition assays, RT-PCR, glutamate uptake assay in primary human astrocytes Journal of neurochemistry Medium 14713304
2011 GLAST/EAAT1 transport activity triggers mTOR phosphorylation (Ser2448) and downstream signaling in Bergmann glia. D-aspartate and other transported substrates (but not non-transported ligands) activate a cascade involving Ca2+ influx, PI3K, and PKB, leading to increased AP-1 DNA binding and upregulation of AP-1-driven transcription. Primary chick cerebellar Bergmann glia, D-aspartate and transporter ligand treatments, mTOR phosphorylation assays, pharmacological inhibitors, AP-1 reporter gene assays Neurochemistry international Medium 21856347
2007 GDNF upregulates GLAST-1 expression via phosphoinositide-3 kinase (PI3K) and Src kinase activity; neurturin upregulates GLAST-1 via PI3K alone. RNA interference demonstrating that GLAST-1 upregulation by GDNF and neurturin is required for their neuroprotective rescue of retinal ganglion cells after optic nerve transection, establishing GLAST-1 upregulation as an indirect neuroprotective mechanism. Adult rat retina, GDNF/NTN intravitreal application, PI3K and Src kinase inhibitors, siRNA knockdown of GLAST-1, RGC survival counting after optic nerve transection Cell death and differentiation Medium 18064044
2010 P2X7 receptor activation by ATP decreases GLAST mRNA stability in astrocytes via a Ca2+-dependent PI3K–PLCγ–IP3R–CaMKII–PKC signaling cascade. This mechanism was demonstrated by P2X7R blockade, P2X7R siRNA knockdown, promoter deletion assays, and RNA decay assays. Primary rat cortical astrocytes, ATP and BzATP treatment, P2X7R antagonist (oxATP) and shRNA knockdown, GLAST promoter deletion assays, RNA decay assays, Ca2+ chelation, pharmacological pathway inhibitors Journal of neurochemistry High 20070863
2014 GSK3β differentially regulates GLT-1 and GLAST: in heterologous expression systems (COS-7 cells and Xenopus oocytes), GSK3β stimulates GLT-1 activity and reduces GLAST activity, with corresponding changes in plasma membrane amounts. GSK3β increases phosphorylation of GLAST while decreasing that of GLT-1. Pharmacological GSK3β inhibition in primary rat cortical cultures also differentially modulates the two transporters. COS-7 cell and Xenopus oocyte heterologous expression, transporter activity assays, plasma membrane quantification, 32Pi incorporation (phosphorylation), GSK3β inhibitors and dominant-negative kinase, primary rat cortical astrocyte cultures Neurochemistry international Medium 25454285
2018 p53 promotes expression of SLC1A3, an aspartate/glutamate transporter, under glutamine deprivation. SLC1A3 expression maintains electron transport chain and TCA cycle activity and supports de novo glutamate, glutamine, and nucleotide synthesis to rescue cell viability. SLC1A3 depletion retards tumor growth in vitro and in vivo, establishing SLC1A3 as a mediator of p53-dependent metabolic adaptation. Cell viability assays, metabolic flux analysis (isotope tracing), xenograft tumor growth, SLC1A3 knockdown and overexpression, p53 reporter and ChIP-inferred transcriptional regulation Cell metabolism High 30122553
2019 SLC1A3 mediates aspartate/glutamate uptake that fuels ASNase resistance in solid tumor cells by supporting TCA cycle, urea cycle, nucleotide biosynthesis, energy production, redox homeostasis, and lipid biosynthesis. In vivo, SLC1A3 expression promoted tumor development and metastasis while negating ASNase suppressive effects. Functional genetic screen, siRNA/shRNA knockdown, cell cycle and apoptosis assays, metabolic profiling, xenograft tumor models in mice The EMBO journal High 31523835
2010 In Drosophila, Eaat1 (ortholog of mammalian GLAST/EAAT1) expression in CNS glia is regulated by the glycosyltransferase Fringe via Delta-Notch ligand-receptor signaling from neurons to glia during embryogenesis. Loss-of-function Eaat1 mutations cause failure of rhythmic peristaltic crawling in larvae, associated with altered synaptic current frequency, amplitude, and kinetics in motor neurons, establishing Eaat1 as essential for glutamate homeostasis in CNS circuits controlling locomotion. Drosophila genetics (loss-of-function mutations, Fringe/Notch pathway manipulation), electrophysiology of motor neuron synaptic currents, behavioral locomotion assays, postembryonic inactivation experiments The Journal of neuroscience High 20980602
2018 During hair growth, SLC1A3 is transiently upregulated in proliferating stem/progenitor cells in hair follicle bulge, sebaceous gland, and interfollicular epidermis. Deletion of slc1a3 delays hair follicle anagen entry and uncouples IFE and SG expansion from the hair cycle. Modulation of metabotropic glutamate receptor 5 (mGluR5) activity mimics the effects of SLC1A3 deletion or inhibition, suggesting SLC1A3 acts upstream of mGluR5 signaling to coordinate stem/progenitor cell activation across skin niches. Transgenic fate-mapping in mice, slc1a3 conditional knockout, BrdU/Ki67 proliferation assays, pharmacological mGluR5 modulation, hair cycle staging The EMBO journal High 29615452
2007 Amitriptyline induces trafficking of GLAST and GLT-1 from cytosol onto the glial cell surface in morphine-tolerant rats by inhibiting phospho-PKA and PKC (PKCα, PKCβII, PKCγ) expression; the same PKA/PKC inhibitors alone also induced GLAST/GLT-1 trafficking. This trafficking correlates with suppression of morphine-evoked EAA (glutamate, aspartate) release in spinal CSF. Intrathecal morphine-tolerant rat model, antinociception dose-response curves, PKA/PKC inhibitor treatments, synaptosomal surface biotinylation, Western blot of GLAST/GLT-1 cytosol vs. membrane, microdialysis/amino acid measurement in CSF Pain Medium 17346885
2002 GLAST-1 protein localizes to the plasma membrane of osteocytes in a glutamate-concentration-dependent manner: low extracellular glutamate redistributes GLAST-1-GFP to intracellular vesicles, while a splice variant (GLAST-1a, lacking exon 3) constitutively localizes to internal vesicles and does not traffic to the plasma membrane. Transfection of GFP-tagged GLAST-1 and GLAST-1a into MLO-Y4 osteocytes, fluorescence microscopy, RT-PCR Biochemical Society transactions Low 12440940
2019 In glioblastoma (GBM) stem-like cells, GLAST is expressed but cells release rather than take up glutamate due to lack of Na+/K+-ATPase. Overexpression of Na+/K+-ATPase in GBM stem-like cells restores glutamate uptake and induces apoptosis, demonstrating that GLAST transport direction in tumor cells depends on Na+/K+-ATPase activity. Intratumoral injection of GLAST inhibitor UCPH-101 significantly increased survival of glioma-bearing mice. GBM stem cell cultures, Na+/K+-ATPase overexpression, glutamate release/uptake assays, apoptosis assays, MR spectroscopy, mouse xenograft with UCPH-101 treatment International journal of cancer Medium 30418668
2006 GLAST/EAAT1 regulates cell-surface expression of the neutral amino acid transporter ASCT2 in human fetal astrocytes: glutamate transported by GLAST is converted to glutamine by glutamine synthetase (GS), and this intracellular glutamine is a more potent inducer of ASCT2 trafficking to the cell surface than direct ASCT2 substrates. siRNA knockdown of GS abolished the glutamate-dependent ASCT2 trafficking effect. Primary human fetal astrocyte cultures, cAMP-induced differentiation, siRNA knockdown of GS, biotinylation of surface proteins, fluorescence microscopy, TFB-TBOA transporter block Neurochemistry international Medium 16516348
2021 Chronic optogenetic activation of Bergmann glia reduces EAAT1 function, prolongs excitatory postsynaptic currents in Purkinje cells, and causes astroglyosis and Purkinje cell atrophy—phenotypes identical to those caused by expression of polyglutamine-expanded ataxin-1 in Bergmann glia, establishing that excessive glutamate signaling from EAAT1 dysfunction is a driver of SCA1-like cerebellar neurodegeneration. Mouse Bergmann glia-targeted optogenetics (ChR2), patch clamp recordings of EPSC kinetics in Purkinje cells, histological analysis of astroglyosis and Purkinje cell atrophy, comparison with ataxin-1[Q85] and ataxin-1[Q154] knock-in mouse models Neurobiology of disease Medium 33753288
1996 The mouse Slc1a3 gene spans >56 kb with 10 exons, maps to chromosome 15A2, and contains a CCAAT box and GC box (but no TATA box) in its promoter. A 4-kb 5'-flanking region drives luciferase expression in COS-1 cells; deletion to 619 bp causes a marked decrease, identifying the CCAAT box at −200 as necessary for expression. Genomic library screening, restriction mapping, primer extension, promoter-luciferase reporter assays in COS-1 cells, in situ hybridization chromosomal localization Genomics Medium 8661010

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics. Neuropharmacology 362 30851309
1997 Glutamate transporter GLAST is expressed in the radial glia-astrocyte lineage of developing mouse spinal cord. The Journal of neuroscience : the official journal of the Society for Neuroscience 323 9364068
2005 Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 272 16116111
1999 Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. The Journal of neuroscience : the official journal of the Society for Neuroscience 261 10575016
1995 Coincidence of L-glutamate/L-aspartate transporter (GLAST) and glutamine synthetase (GS) immunoreactions in retinal glia: evidence for coupling of GLAST and GS in transmitter clearance. Journal of neuroscience research 215 8531222
1997 Neuronal soluble factors differentially regulate the expression of the GLT1 and GLAST glutamate transporters in cultured astroglia. Journal of neurochemistry 198 9375696
2018 A Role for p53 in the Adaptation to Glutamine Starvation through the Expression of SLC1A3. Cell metabolism 196 30122553
1998 Traumatic brain injury down-regulates glial glutamate transporter (GLT-1 and GLAST) proteins in rat brain. Journal of neurochemistry 176 9572288
2000 The GLT-1 and GLAST glutamate transporters are expressed on morphologically distinct astrocytes and regulated by neuronal activity in primary hippocampal cocultures. Journal of neurochemistry 159 10936189
2005 Regulation of glutamate transporter GLAST and GLT-1 expression in astrocytes by estrogen. Brain research. Molecular brain research 154 15896872
1996 Glutamate receptor agonists up-regulate glutamate transporter GLAST in astrocytes. Neuroreport 145 9051792
2008 Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 143 19078949
2002 Aberrant expression of the glutamate transporter excitatory amino acid transporter 1 (EAAT1) in Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 106 11826152
2009 Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation. Molecular pain 104 19323820
2018 Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders. World journal of psychiatry 103 29988908
2013 In vivo contribution of nestin- and GLAST-lineage cells to adult hippocampal neurogenesis. Hippocampus 96 23554226
2003 Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B. Journal of neurochemistry 96 12911626
2009 Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake. Archives of neurology 95 19139306
2010 ASK1 deficiency attenuates neural cell death in GLAST-deficient mice, a model of normal tension glaucoma. Cell death and differentiation 85 20489729
2001 Differential distribution of the glutamate transporters GLT-1 and GLAST in tanycytes of the third ventricle. The Journal of comparative neurology 82 11283952
2000 Distribution of the glutamate transporters GLAST and GLT-1 in rat circumventricular organs, meninges, and dorsal root ganglia. The Journal of comparative neurology 81 10813794
2000 Fine tuning of glutamate uptake and degradation in glial cells: common transcriptional regulation of GLAST1 and GS. Neurochemistry international 72 10812203
2004 Glutamate transporters in platelets: EAAT1 decrease in aging and in Alzheimer's disease. Neurobiology of aging 71 14749132
2001 Na+ dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) in primary astrocyte cultures: effect of oxidative stress. Brain research 69 11730698
2010 Drosophila glial glutamate transporter Eaat1 is regulated by fringe-mediated notch signaling and is essential for larval locomotion. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 20980602
2019 SLC1A3 contributes to L-asparaginase resistance in solid tumors. The EMBO journal 61 31523835
2015 Transcriptional Regulation of the Astrocytic Excitatory Amino Acid Transporter 1 (EAAT1) via NF-κB and Yin Yang 1 (YY1). The Journal of biological chemistry 61 26269591
2014 Localization of excitatory amino acid transporters EAAT1 and EAAT2 in human postmortem cortex: a light and electron microscopic study. Neuroscience 61 25064059
2009 Effects of hyperglycemia and oxidative stress on the glutamate transporters GLAST and system xc- in mouse retinal Müller glial cells. Cell and tissue research 61 19156441
2020 SLC1A3 promotes gastric cancer progression via the PI3K/AKT signalling pathway. Journal of cellular and molecular medicine 58 33145952
2007 Amitriptyline preserves morphine's antinociceptive effect by regulating the glutamate transporter GLAST and GLT-1 trafficking and excitatory amino acids concentration in morphine-tolerant rats. Pain 57 17346885
2003 Transcriptional regulation of human excitatory amino acid transporter 1 (EAAT1): cloning of the EAAT1 promoter and characterization of its basal and inducible activity in human astrocytes. Journal of neurochemistry 57 14713304
2011 Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms. Behavioral and brain functions : BBF 56 21711518
2009 Excitatory amino acid transporters EAAT-1 and EAAT-2 in temporal lobe and hippocampus in intractable temporal lobe epilepsy. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 56 19338517
2007 The upregulation of GLAST-1 is an indirect antiapoptotic mechanism of GDNF and neurturin in the adult CNS. Cell death and differentiation 56 18064044
2007 Expression of EAAT1 reflects a possible neuroprotective function of reactive astrocytes and activated microglia following human traumatic brain injury. Histology and histopathology 54 17330806
2007 Reactive astrocytes and activated microglial cells express EAAT1, but not EAAT2, reflecting a neuroprotective potential following ischaemia. Histopathology 53 17543080
2014 Laminar and subcellular heterogeneity of GLAST and GLT-1 immunoreactivity in the developing postnatal mouse hippocampus. The Journal of comparative neurology 51 23939750
2008 Expression and distribution of 'high affinity' glutamate transporters GLT1, GLAST, EAAC1 and of GCPII in the rat peripheral nervous system. Journal of anatomy 51 19014361
1997 Expression of glial glutamate transporters GLT-1 and GLAST is unchanged in the hippocampus in fully kindled rats. Neuroscience 50 9145792
1998 Expression of two glutamate transporters, GLAST and EAAT4, in the human cerebellum: their correlation in development and neonatal hypoxic-ischemic damage. Journal of neuropathology and experimental neurology 49 9630235
2011 Genetic and functional studies of a missense variant in a glutamate transporter, SLC1A3, in Tourette syndrome. Psychiatric genetics 47 21233784
2007 Glutamate-dependent transcriptional regulation of GLAST/EAAT1: a role for YY1. Journal of neurochemistry 47 17394550
2006 Glutamate transporters GLAST and EAAT4 regulate postischemic Purkinje cell death: an in vivo study using a cardiac arrest model in mice lacking GLAST or EAAT4. Neuroscience research 47 16647773
2015 GLAST But Not Least--Distribution, Function, Genetics and Epigenetics of L-Glutamate Transport in Brain--Focus on GLAST/EAAT1. Neurochemical research 46 25972039
2018 Valproic acid attenuates manganese-induced reduction in expression of GLT-1 and GLAST with concomitant changes in murine dopaminergic neurotoxicity. Neurotoxicology 45 29778792
2007 Glutamate transporter GLAST/EAAT1 directs cell surface expression of FXYD2/gamma subunit of Na, K-ATPase in human fetal astrocytes. Neurochemistry international 44 17316900
2012 BDNF regulates GLAST and glutamine synthetase in mouse retinal Müller cells. Journal of cellular physiology 43 21448920
2004 Differential regulation of GLAST immunoreactivity and activity by protein kinase C: evidence for modification of amino and carboxyl termini. Journal of neurochemistry 43 15569258
2007 Association study of polymorphisms in the glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 with schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 42 17221839
2003 Glutamate down-regulates GLAST expression through AMPA receptors in Bergmann glial cells. Brain research. Molecular brain research 42 12824049
2000 Modulation of glutamate transporters (GLAST, GLT-1 and EAAC1) in the rat cerebellum following portocaval anastomosis. Brain research 42 10719077
2008 Expression of glutamate transporters GLT-1 and GLAST in different regions of rat brain during the course of experimental autoimmune encephalomyelitis. Neuroscience 41 18572325
1996 Genomic organization, promoter analysis, and chromosomal localization of the gene for the mouse glial high-affinity glutamate transporter Slc1a3. Genomics 40 8661010
2019 In vivo knockdown of astroglial glutamate transporters GLT-1 and GLAST increases excitatory neurotransmission in mouse infralimbic cortex: Relevance for depressive-like phenotypes. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 38 31582286
2017 Arundic Acid Increases Expression and Function of Astrocytic Glutamate Transporter EAAT1 Via the ERK, Akt, and NF-κB Pathways. Molecular neurobiology 38 28812276
2016 Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 38 27476799
2010 The food-associated fungal neurotoxin ochratoxin A inhibits the absorption of glutamate by astrocytes through a decrease in cell surface expression of the excitatory amino-acid transporters GLAST and GLT-1. Neurotoxicology 38 20558201
2002 The expression of the glutamate re-uptake transporter excitatory amino acid transporter 1 (EAAT1) in the normal human CNS and in motor neurone disease: an immunohistochemical study. Neuroscience 38 11784698
2023 Glial Glutamate Transporter-Mediated Plasticity: System xc-/xCT/SLC7A11 and EAAT1/2 in Brain Diseases. Frontiers in bioscience (Landmark edition) 36 37005761
2018 Glutamate transporter Slc1a3 mediates inter-niche stem cell activation during skin growth. The EMBO journal 36 29615452
2016 Late-onset episodic ataxia associated with SLC1A3 mutation. Journal of human genetics 36 27829685
2008 Valproate-dependent transcriptional regulation of GLAST/EAAT1 expression: involvement of Ying-Yang 1. Neurochemistry international 36 18336953
2013 Primary cultures of rat cortical microglia treated with nicotine increases in the expression of excitatory amino acid transporter 1 (GLAST) via the activation of the α7 nicotinic acetylcholine receptor. Neuroscience 34 24300109
2018 Loss of cerebellar glutamate transporters EAAT4 and GLAST differentially affects the spontaneous firing pattern and survival of Purkinje cells. Human molecular genetics 33 29741614
2017 Impaired K+ binding to glial glutamate transporter EAAT1 in migraine. Scientific reports 33 29066757
2000 EAAT1 is involved in transport of L-glutamate during differentiation of the Caco-2 cell line. American journal of physiology. Gastrointestinal and liver physiology 32 10915646
2019 Altered function of the glutamate-aspartate transporter GLAST, a potential therapeutic target in glioblastoma. International journal of cancer 31 30418668
2020 Functional consequences of SLC1A3 mutations associated with episodic ataxia 6. Human mutation 30 32741053
2019 Regulation of Synaptosomal GLT-1 and GLAST during Epileptogenesis. Neuroscience 30 31158434
2004 Expression of excitatory amino acid transporter-1 (EAAT-1) in brain macrophages and microglia of patients with prion diseases. Journal of neuropathology and experimental neurology 29 15535133
2017 A novel mutation in SLC1A3 causes episodic ataxia. Journal of human genetics 28 29208948
2011 Signaling through EAAT-1/GLAST in cultured Bergmann glia cells. Neurochemistry international 27 21856347
2008 Inhibitory regulation of glutamate aspartate transporter (GLAST) expression in astrocytes by cadmium-induced calcium influx. Journal of neurochemistry 27 18371048
2005 Methylmercury alters the in vitro uptake of glutamate in GLAST- and GLT-1-transfected mutant CHO-K1 cells. Biological trace element research 27 16286679
2018 Targeting β-Catenin in GLAST-Expressing Cells: Impact on Anxiety and Depression-Related Behavior and Hippocampal Proliferation. Molecular neurobiology 26 29737454
2011 Arsenite exposure downregulates EAAT1/GLAST transporter expression in glial cells. Toxicological sciences : an official journal of the Society of Toxicology 26 21602192
2010 Ca(2+)-dependent reduction of glutamate aspartate transporter GLAST expression in astrocytes by P2X(7) receptor-mediated phosphoinositide 3-kinase signaling. Journal of neurochemistry 26 20070863
2022 SLC1A3 facilitates Newcastle disease virus replication by regulating glutamine catabolism. Virulence 25 35993169
2005 A family based study implicates solute carrier family 1-member 3 (SLC1A3) gene in attention-deficit/hyperactivity disorder. Biological psychiatry 25 15950021
2015 Thrombin decreases expression of the glutamate transporter GLAST and inhibits glutamate uptake in primary cortical astrocytes via the Rho kinase pathway. Experimental neurology 24 26391563
2007 Regulation of the mGluR5, EAAT1 and GS expression by glucocorticoids in MG-63 osteoblast-like osteosarcoma cells. Journal of musculoskeletal & neuronal interactions 24 17627080
1996 Human high affinity, Na(+)-dependent L-glutamate/L-aspartate transporter GLAST-1 (EAAT-1): gene structure and localization to chromosome 5p11-p12. FEBS letters 24 8647279
2019 CD133 promotes the self-renewal capacity of thyroid cancer stem cells through activation of glutamate aspartate transporter SLC1A3 expression. Biochemical and biophysical research communications 23 30771902
2016 Duplications of SLC1A3: Associated with ADHD and autism. European journal of medical genetics 22 27296938
2014 Pharmacological inhibitions of glutamate transporters EAAT1 and EAAT2 compromise glutamate transport in photoreceptor to ON-bipolar cell synapses. Vision research 22 25152321
2007 Subcellular localization of the glutamate transporters GLAST and GLT at the neuromuscular junction in rodents. Neuroscience 22 17289278
2002 The glutamate transporter GLAST-1 (EAAT-1) is expressed in the plasma membrane of osteocytes and is responsive to extracellular glutamate concentration. Biochemical Society transactions 22 12440940
2017 Constitutive regulation of the glutamate/aspartate transporter EAAT1 by Calcium-Calmodulin-Dependent Protein Kinase II. Journal of neurochemistry 21 27889915
2009 Differential expression of two glutamate transporters, GLAST and GLT-1, in an experimental rat model of glaucoma. Experimental brain research 21 19551376
2006 High-affinity glutamate transporter GLAST/EAAT1 regulates cell surface expression of glutamine/neutral amino acid transporter ASCT2 in human fetal astrocytes. Neurochemistry international 21 16516348
2012 Transcriptional regulation of the GLAST/EAAT-1 gene in rat and man. Cellular and molecular neurobiology 20 22252783
2005 In vitro uptake of glutamate in GLAST- and GLT-1-transfected mutant CHO-K1 cells is inhibited by the ethylmercury-containing preservative thimerosal. Biological trace element research 20 16034155
2021 Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1. Neurobiology of disease 19 33753288
2014 Differential regulation of the glutamate transporters GLT-1 and GLAST by GSK3β. Neurochemistry international 19 25454285
2004 Ethanol induces expression of the glutamate transporters EAAT1 and EAAT2 in organotypic cortical slice cultures. Alcoholism, clinical and experimental research 19 15547463
2002 Expression of glutamate transporters and ionotropic glutamate receptors in GLAST knockout mice. Brain research. Molecular brain research 19 12225864
2007 EAAT1 and D-serine expression are early features of human retinal development. Experimental eye research 18 17379211
1998 The L-glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2): expression and regulation in rat lactating mammary gland. Molecular membrane biology 18 10087511
1994 The mouse and human excitatory amino acid transporter gene (EAAT1) maps to mouse chromosome 15 and a region of syntenic homology on human chromosome 5. Genomics 18 8001975

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