Glutamate aspartate transporter

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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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RefSeq (mRNA)

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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.[1] 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.[2] It has also been localized in the inner mitochondrial membrane as part of the malate-aspartate shuttle.[3]

Mechanism

GLAST functions in vivo as a homotrimer.[4] 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.[5]

Tissue distribution

GLAST is expressed throughout the CNS,[6] and is highly expressed in astrocytes and Bergmann glia in the cerebellum.[7][8] In the retina, GLAST is expressed in Muller cells.[9] GLAST is also expressed in a number of other tissues including cardiac myocytes.[3]

Clinical significance

It is associated with type 6 episodic_ataxia.[10]

Pharmacology

DL-threo-beta-benzyloxyaspartate (TBOA) is an inhibitor of the excitatory amino acid transporters.[11]

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.[12]

References

  1. "Entrez Gene: SLC1A3 solute carrier family 1 (glial high affinity glutamate transporter), member 3".
  2. Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC (March 1995). "Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations". The Journal of Neuroscience. 15 (3 Pt 1): 1835–53. PMID 7891138.
  3. 3.0 3.1 Ralphe JC, Segar JL, Schutte BC, Scholz TD (2004). "Localization and function of the brain excitatory amino acid transporter type 1 in cardiac mitochondria". J. Mol. Cell. Cardiol. 37 (1): 33–41. doi:10.1016/j.yjmcc.2004.04.008. PMID 15242733.
  4. Gendreau S, Voswinkel S, Torres-Salazar D, Lang N, Heidtmann H, Detro-Dassen S, Schmalzing G, Hidalgo P, Fahlke C (Sep 17, 2004). "A trimeric quaternary structure is conserved in bacterial and human glutamate transporters". The Journal of Biological Chemistry. 279 (38): 39505–12. doi:10.1074/jbc.M408038200. PMID 15265858.
  5. Kanai Y, Hediger MA (2004). "The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects". Pflügers Arch. 447 (5): 469–79. doi:10.1007/s00424-003-1146-4. PMID 14530974.
  6. Danbolt NC (September 2001). "Glutamate uptake". Prog. Neurobiol. 65 (1): 1–105. doi:10.1016/S0301-0082(00)00067-8. PMID 11369436.
  7. Storck T, Schulte S, Hofmann K, Stoffel W (1992). "Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain". Proc. Natl. Acad. Sci. U.S.A. 89 (22): 10955–9. doi:10.1073/pnas.89.22.10955. PMC 50461. PMID 1279699.
  8. Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, Nash N, Kuncl RW (1994). "Localization of neuronal and glial glutamate transporters". Neuron. 13 (3): 713–25. doi:10.1016/0896-6273(94)90038-8. PMID 7917301.
  9. Rauen T, Taylor WR, Kuhlbrodt K, Wiessner M (1998). "High-affinity glutamate transporters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in transmitter clearance". Cell Tissue Res. 291 (1): 19–31. doi:10.1007/s004410050976. PMID 9394040.
  10. Jen JC, Wan J, Palos TP, Howard BD, Baloh RW (2005). "Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures". Neurology. 65 (4): 529–34. doi:10.1212/01.WNL.0000172638.58172.5a. PMID 16116111.
  11. Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T (February 1998). "DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters". Molecular Pharmacology. 53 (2): 195–201. PMID 9463476.
  12. Jensen AA, Erichsen MN, Nielsen CW, Stensbøl TB, Kehler J, Bunch L (Feb 26, 2009). "Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1". Journal of Medicinal Chemistry. 52 (4): 912–5. doi:10.1021/jm8013458. PMID 19161278.

Further reading

External links


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