Excitatory amino acid transporter 1
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.[5] 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.[6] It has also been localized in the inner mitochondrial membrane as part of the malate-aspartate shuttle.[7]
Mechanism
GLAST functions in vivo as a homotrimer.[8] 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.[9]
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"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.
Tissue distribution
GLAST is expressed throughout the CNS,[10] and is highly expressed in astrocytes and Bergmann glia in the cerebellum.[11][12] In the retina, GLAST is expressed in Muller cells.[13] GLAST is also expressed in a number of other tissues including cardiac myocytes.[7]
Clinical significance
It is associated with type 6 episodic_ataxia.[14]
Pharmacology
DL-threo-beta-benzyloxyaspartate (TBOA) is an inhibitor of the excitatory amino acid transporters.[15]
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.[16]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000079215 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005360 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: SLC1A3 solute carrier family 1 (glial high affinity glutamate transporter), member 3".
- ^ 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.
- ^ a b 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.
- ^ 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.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ 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.
- ^ Danbolt NC (September 2001). "Glutamate uptake". Prog. Neurobiol. 65 (1): 1–105. doi:10.1016/S0301-0082(00)00067-8. PMID 11369436.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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
- 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 U.S. National Library of Medicine Medical Subject Headings (MeSH)