Glutamate aspartate transporter

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Species	Human	Mouse
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Solute carrier family 1 (glial high-affinity glutamate transporter), member 3, also known as SLC1A3, is a protein that, in humans, is encoded by the SLC1A3 gene. SLC1A3 is also often called the GLutamate ASpartate Transporter (GLAST) or Excitatory Amino Acid Transporter 1 (EAAT1) .

GLAST is predominantly expressed in the plasma membrane, allowing it to remove glutamate from the extracellular space. It has also been localized in the inner mitochondrial membrane as part of the malate-aspartate shuttle.

Mechanism

GLAST functions in vivo as a homotrimer. GLAST mediates the transport of glutamic and aspartic acid with the cotransport of three Na⁺ and one H⁺ cations and counter transport of one K⁺ cation. This co-transport coupling (or symport) allows the transport of glutamate into cells against a concentration gradient.

• "Diagram Illustrating the Malate-Aspartate Shuttle Pathway". (Glutamate aspartate transporter labeled at bottom center.)

  "Diagram Illustrating the Malate-Aspartate Shuttle Pathway". (Glutamate aspartate transporter labeled at bottom center.)

• Expression of SLC1A3 in the Bergmann glia fibers. Mouse brain at 7th postnatal day, sagittal section; GENSAT database.

  Expression of SLC1A3 in the Bergmann glia fibers. Mouse brain at 7th postnatal day, sagittal section; GENSAT database.

Tissue distribution

GLAST is expressed throughout the CNS, and is highly expressed in astrocytes and Bergmann glia in the cerebellum. In the retina, GLAST is expressed in Muller cells. GLAST is also expressed in a number of other tissues including cardiac myocytes.

Clinical significance

It is associated with type 6 episodic_ataxia.

Pharmacology

DL-threo-beta-benzyloxyaspartate (TBOA) is an inhibitor of the excitatory amino acid transporters.

Selective inhibitors for GLAST have recently been discovered based on 25 combinations of substitutions at the 4 and 7 positions of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitril.

Further reading

• Arriza JL, Fairman WA, Wadiche JI, et al. (1994). "Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex". J. Neurosci. 14 (9): 5559–69. PMID 7521911.
• Nomura N, Nagase T, Miyajima N, et al. (1995). "Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1". DNA Res. 1 (5): 223–9. doi:10.1093/dnares/1.5.223. PMID 7584044.
• Takai S, Yamada K, Kawakami H, et al. (1995). "Localization of the gene (SLC1A3) encoding human glutamate transporter (GluT-1) to 5p13 by fluorescence in situ hybridization". Cytogenet. Cell Genet. 69 (3–4): 209–10. doi:10.1159/000133965. PMID 7698014.
• Shashidharan P, Huntley GW, Meyer T, et al. (1995). "Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain". Brain Res. 662 (1–2): 245–50. doi:10.1016/0006-8993(94)90819-2. PMID 7859077.
• Kirschner MA, Arriza JL, Copeland NG, et al. (1995). "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. 22 (3): 631–3. doi:10.1006/geno.1994.1437. PMID 8001975.
• Kawakami H, Tanaka K, Nakayama T, et al. (1994). "Cloning and expression of a human glutamate transporter". Biochem. Biophys. Res. Commun. 199 (1): 171–6. doi:10.1006/bbrc.1994.1210. PMID 8123008.
• Shashidharan P, Plaitakis A (1993). "Cloning and characterization of a glutamate transporter cDNA from human cerebellum". Biochim. Biophys. Acta. 1216 (1): 161–4. doi:10.1016/0167-4781(93)90057-K. PMID 8218410.
• Andersson B, Wentland MA, Ricafrente JY, et al. (1996). "A "double adaptor" method for improved shotgun library construction". Anal. Biochem. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
• Stoffel W, Sasse J, Düker M, et al. (1996). "Human high affinity, Na(+)-dependent L-glutamate/L-aspartate transporter GLAST-1 (EAAT-1): gene structure and localization to chromosome 5p11-p12". FEBS Lett. 386 (2–3): 189–93. doi:10.1016/0014-5793(96)00424-3. PMID 8647279.
• Yu W, Andersson B, Worley KC, et al. (1997). "Large-scale concatenation cDNA sequencing". Genome Res. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• Dunlop J, Lou Z, McIlvain HB (1999). "Properties of excitatory amino acid transport in the human U373 astrocytoma cell line". Brain Res. 839 (2): 235–42. doi:10.1016/S0006-8993(99)01714-X. PMID 10519046.
• Koch HP, Kavanaugh MP, Esslinger CS, et al. (1999). "Differentiation of substrate and nonsubstrate inhibitors of the high-affinity, sodium-dependent glutamate transporters". Mol. Pharmacol. 56 (6): 1095–104. PMID 10570036.
• Ye ZC, Rothstein JD, Sontheimer H (2000). "Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange". J. Neurosci. 19 (24): 10767–77. PMID 10594060.
• Szymocha R, Akaoka H, Dutuit M, et al. (2000). "Human T-cell lymphotropic virus type 1-infected T lymphocytes impair catabolism and uptake of glutamate by astrocytes via Tax-1 and tumor necrosis factor alpha". J. Virol. 74 (14): 6433–41. doi:10.1128/JVI.74.14.6433-6441.2000. PMC 112151. PMID 10864655.
• Mordrelle A, Jullian E, Costa C, et al. (2000). "EAAT1 is involved in transport of L-glutamate during differentiation of the Caco-2 cell line". Am. J. Physiol. Gastrointest. Liver Physiol. 279 (2): G366–73. PMID 10915646.
• Seal RP, Shigeri Y, Eliasof S, et al. (2002). "Sulfhydryl modification of V449C in the glutamate transporter EAAT1 abolishes substrate transport but not the substrate-gated anion conductance". Proc. Natl. Acad. Sci. U.S.A. 98 (26): 15324–9. doi:10.1073/pnas.011400198. PMC 65028. PMID 11752470.
• Palmada M, Kinne-Saffran E, Centelles JJ, Kinne RK (2002). "Benzodiazepines differently modulate EAAT1/GLAST and EAAT2/GLT1 glutamate transporters expressed in CHO cells". Neurochem. Int. 40 (4): 321–6. doi:10.1016/S0197-0186(01)00087-0. PMID 11792462.
• Scott HL, Pow DV, Tannenberg AE, Dodd PR (2002). "Aberrant expression of the glutamate transporter excitatory amino acid transporter 1 (EAAT1) in Alzheimer's disease". J. Neurosci. 22 (3): RC206. PMID 11826152.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Vallat-Decouvelaere AV, Chrétien F, Gras G, et al. (2003). "Expression of excitatory amino acid transporter-1 in brain macrophages and microglia of HIV-infected patients. A neuroprotective role for activated microglia?". J. Neuropathol. Exp. Neurol. 62 (5): 475–85. PMID 12769187.

External links

• Glutamate+Aspartate+Transporter+1 at the US National Library of Medicine Medical Subject Headings (MeSH)