View source for Glutamate aspartate transporter

{{Infobox gene}}

'''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]].<ref name="entrez">{{cite web | title = Entrez Gene: SLC1A3 solute carrier family 1 (glial high affinity glutamate transporter), member 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6507| accessdate = }}</ref>  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.<ref>{{cite journal |vauthors=Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC | title = Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. | journal = The Journal of Neuroscience | volume = 15 | issue = 3 Pt 1 | pages = 1835–53 | date = March 1995 | pmid = 7891138 }}</ref>  It has also been localized in the [[inner mitochondrial membrane]] as part of the [[malate-aspartate shuttle]].<ref name="pmid15242733">{{cite journal |vauthors=Ralphe JC, Segar JL, Schutte BC, Scholz TD | title = Localization and function of the brain excitatory amino acid transporter type 1 in cardiac mitochondria | journal = J. Mol. Cell. Cardiol. | volume = 37 | issue = 1 | pages = 33–41 | year = 2004 | pmid = 15242733 | doi = 10.1016/j.yjmcc.2004.04.008 }}</ref>

== Mechanism ==

GLAST functions ''in vivo'' as a [[homotrimer]].<ref>{{cite journal |vauthors=Gendreau S, Voswinkel S, Torres-Salazar D, Lang N, Heidtmann H, Detro-Dassen S, Schmalzing G, Hidalgo P, Fahlke C | title = A trimeric quaternary structure is conserved in bacterial and human glutamate transporters. | journal = The Journal of Biological Chemistry | volume = 279 | issue = 38 | pages = 39505–12 | date = Sep 17, 2004 | pmid = 15265858 | doi = 10.1074/jbc.M408038200  }}</ref>  GLAST mediates the transport of [[glutamic acid|glutamic]] and [[aspartic acid]] with the [[Co-transport|cotransport]] of three [[sodium|Na<sup>+</sup>]] and one [[proton|H<sup>+</sup>]] [[ion|cations]] and counter transport of one [[potassium|K<sup>+</sup>]] cation.  This co-transport coupling (or [[symport]]) allows the transport of glutamate into cells against a concentration gradient.<ref name="pmid14530974">{{cite journal |vauthors=Kanai Y, Hediger MA | title = The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects | journal = Pflugers Arch. | volume = 447 | issue = 5 | pages = 469–79 | year = 2004 | pmid = 14530974 | doi = 10.1007/s00424-003-1146-4 }}</ref>

{{Gallery
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|Image:Malate-aspartate shuttle.png|"Diagram Illustrating the Malate-Asparate Shuttle Pathway". (Glutamate aspartate transporter labeled at bottom center.)
|Image:Slcla3 in Bergmann Glia.jpg|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 [[Central nervous system|CNS]],<ref name="pmid11369436">{{cite journal | author = Danbolt NC | title = Glutamate uptake | journal = Prog. Neurobiol. | volume = 65 | issue = 1 | pages = 1–105 | date = September 2001 | pmid = 11369436 | doi = 10.1016/S0301-0082(00)00067-8 }}</ref> and is highly expressed in [[astrocyte]]s and [[Bergmann glia]] in the [[cerebellum]].<ref name="pmid1279699">{{cite journal |vauthors=Storck T, Schulte S, Hofmann K, Stoffel W | title = Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 89 | issue = 22 | pages = 10955–9 | year = 1992 | pmid = 1279699 | pmc = 50461 | doi = 10.1073/pnas.89.22.10955 }}</ref><ref name="pmid7917301">{{cite journal |vauthors=Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, Nash N, Kuncl RW | title = Localization of neuronal and glial glutamate transporters | journal = Neuron | volume = 13 | issue = 3 | pages = 713–25 | year = 1994 | pmid = 7917301 | doi = 10.1016/0896-6273(94)90038-8 }}</ref>  In the retina, GLAST is expressed in [[Muller cell]]s.<ref name="pmid9394040">{{cite journal |vauthors=Rauen T, Taylor WR, Kuhlbrodt K, Wiessner M | title = High-affinity glutamate transporters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in transmitter clearance | journal = Cell Tissue Res. | volume = 291 | issue = 1 | pages = 19–31 | year = 1998 | pmid = 9394040 | doi = 10.1007/s004410050976 }}</ref>  GLAST is also expressed in a number of other tissues including [[cardiac myocytes]].<ref name="pmid15242733"/>

==Clinical significance==
It is associated with type 6 [[Episodic ataxia#EA6: SLC1A3|episodic_ataxia]].<ref name="pmid16116111">{{cite journal |vauthors=Jen JC, Wan J, Palos TP, Howard BD, Baloh RW | title = Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures | journal = Neurology | volume = 65 | issue = 4 | pages = 529–34 | year = 2005 | pmid = 16116111 | doi = 10.1212/01.WNL.0000172638.58172.5a }}</ref>

==Pharmacology==
DL-threo-beta-benzyloxyaspartate (TBOA) is an inhibitor of the excitatory amino acid transporters.<ref>{{cite journal |vauthors=Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T | title = DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters. | journal = Molecular Pharmacology | volume = 53 | issue = 2 | pages = 195–201 | date = February 1998 | pmid = 9463476 }}</ref>

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.<ref>{{cite journal |vauthors=Jensen AA, Erichsen MN, Nielsen CW, Stensbøl TB, Kehler J, Bunch L | title = Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1. | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 4 | pages = 912–5 | date = Feb 26, 2009 | pmid = 19161278 | doi = 10.1021/jm8013458 }}</ref>

==References==
{{Reflist|2}}

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

==External links==
* {{MeshName|Glutamate+Aspartate+Transporter+1}}

{{Membrane transport proteins|bg|bg0}}
{{Mitochondrial enzymes}}
{{Glutamate metabolism and transport modulators}}

[[Category:Solute carrier family]]
[[Category:Neurotransmitter transporters]]
[[Category:Glutamate (neurotransmitter)]]