Excitatory amino acid transporter 1 explained

Excitatory amino acid transporter 1 (EAAT1) is a protein that, in humans, is encoded by the SLC1A3 gene.^[1] EAAT1 is also often called the GLutamate ASpartate Transporter 1 (GLAST-1).

EAAT1 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

EAAT1 functions in vivo as a homotrimer.^[4] EAAT1 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

EAAT1 is expressed throughout the CNS,^[6] and is highly expressed in astrocytes and Bergmann glia in the cerebellum.^{[7] [8]} In the retina, EAAT1 is expressed in Muller cells.^[9] EAAT1 is also expressed in a number of other tissues including cardiac myocytes.^[3]

Clinical significance

It is associated with type 6 episodic ataxia.^[10] EAAT1 expression may also be associated with osteoarthritis.^[11]

Pharmacology

DL-threo-beta-benzyloxyaspartate (TBOA) is an inhibitor of the excitatory amino acid transporters.^[12]

Selective inhibitors for EAAT1 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.^[13]

Further reading

• Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG . Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex . The Journal of Neuroscience . 14 . 9 . 5559–69 . September 1994 . 7521911 . 6577102 . 10.1523/jneurosci.14-09-05559.1994.
• Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S . 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 Research . 1 . 5 . 223–9 . 1995 . 7584044 . 10.1093/dnares/1.5.223 . free .
• Takai S, Yamada K, Kawakami H, Tanaka K, Nakamura S . Localization of the gene (SLC1A3) encoding human glutamate transporter (GluT-1) to 5p13 by fluorescence in situ hybridization . Cytogenetics and Cell Genetics . 69 . 3–4 . 209–10 . 1995 . 7698014 . 10.1159/000133965 .
• Shashidharan P, Huntley GW, Meyer T, Morrison JH, Plaitakis A . Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain . Brain Research . 662 . 1–2 . 245–50 . October 1994 . 7859077 . 10.1016/0006-8993(94)90819-2 . 35811464 .
• Kirschner MA, Arriza JL, Copeland NG, Gilbert DJ, Jenkins NA, Magenis E, Amara SG . 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 . August 1994 . 8001975 . 10.1006/geno.1994.1437 .
• Kawakami H, Tanaka K, Nakayama T, Inoue K, Nakamura S . Cloning and expression of a human glutamate transporter . Biochemical and Biophysical Research Communications . 199 . 1 . 171–6 . February 1994 . 8123008 . 10.1006/bbrc.1994.1210 .
• Shashidharan P, Plaitakis A . Cloning and characterization of a glutamate transporter cDNA from human cerebellum . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1216 . 1 . 161–4 . October 1993 . 8218410 . 10.1016/0167-4781(93)90057-K .
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–13 . April 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Stoffel W, Sasse J, Düker M, Müller R, Hofmann K, Fink T, Lichter P . Human high affinity, Na(+)-dependent L-glutamate/L-aspartate transporter GLAST-1 (EAAT-1): gene structure and localization to chromosome 5p11-p12 . FEBS Letters . 386 . 2–3 . 189–93 . May 1996 . 8647279 . 10.1016/0014-5793(96)00424-3 . 890022 . free .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–8 . April 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Dunlop J, Lou Z, McIlvain HB . Properties of excitatory amino acid transport in the human U373 astrocytoma cell line . Brain Research . 839 . 2 . 235–42 . August 1999 . 10519046 . 10.1016/S0006-8993(99)01714-X . 7021891 .
• Koch HP, Kavanaugh MP, Esslinger CS, Zerangue N, Humphrey JM, Amara SG, Chamberlin AR, Bridges RJ . Differentiation of substrate and nonsubstrate inhibitors of the high-affinity, sodium-dependent glutamate transporters . Molecular Pharmacology . 56 . 6 . 1095–104 . December 1999 . 10570036 . 10.1124/mol.56.6.1095.
• Ye ZC, Rothstein JD, Sontheimer H . Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange . The Journal of Neuroscience . 19 . 24 . 10767–77 . December 1999 . 10594060 . 6784962 . 10.1523/jneurosci.19-24-10767.1999.
• Szymocha R, Akaoka H, Dutuit M, Malcus C, Didier-Bazes M, Belin MF, Giraudon P . 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 of Virology . 74 . 14 . 6433–41 . July 2000 . 10864655 . 112151 . 10.1128/JVI.74.14.6433-6441.2000 .
• Mordrelle A, Jullian E, Costa C, Cormet-Boyaka E, Benamouzig R, Tomé D, Huneau JF . EAAT1 is involved in transport of L-glutamate during differentiation of the Caco-2 cell line . American Journal of Physiology. Gastrointestinal and Liver Physiology . 279 . 2 . G366-73 . August 2000 . 10915646 . 10.1152/ajpgi.2000.279.2.G366 . 45577626 .
• Seal RP, Shigeri Y, Eliasof S, Leighton BH, Amara SG . Sulfhydryl modification of V449C in the glutamate transporter EAAT1 abolishes substrate transport but not the substrate-gated anion conductance . Proceedings of the National Academy of Sciences of the United States of America . 98 . 26 . 15324–9 . December 2001 . 11752470 . 65028 . 10.1073/pnas.011400198 . 2001PNAS...9815324S . free .
• Palmada M, Kinne-Saffran E, Centelles JJ, Kinne RK . Benzodiazepines differently modulate EAAT1/GLAST and EAAT2/GLT1 glutamate transporters expressed in CHO cells . Neurochemistry International . 40 . 4 . 321–6 . April 2002 . 11792462 . 10.1016/S0197-0186(01)00087-0 . 23624873 .
• Scott HL, Pow DV, Tannenberg AE, Dodd PR . Aberrant expression of the glutamate transporter excitatory amino acid transporter 1 (EAAT1) in Alzheimer's disease . The Journal of Neuroscience . 22 . 3 . RC206 . February 2002 . 11826152 . 6758536 . 10.1523/jneurosci.22-03-j0004.2002.
• Vallat-Decouvelaere AV, Chrétien F, Gras G, Le Pavec G, Dormont D, Gray F . Expression of excitatory amino acid transporter-1 in brain macrophages and microglia of HIV-infected patients. A neuroprotective role for activated microglia? . Journal of Neuropathology and Experimental Neurology . 62 . 5 . 475–85 . May 2003 . 12769187 . 10.1093/jnen/62.5.475. 11183438 . free .

Notes and References

1. Web site: 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 . 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 . March 1995 . 7891138 . 6578153 . 10.1523/JNEUROSCI.15-03-01835.1995 .
3. Ralphe JC, Segar JL, Schutte BC, Scholz TD . Localization and function of the brain excitatory amino acid transporter type 1 in cardiac mitochondria . Journal of Molecular and Cellular Cardiology . 37 . 1 . 33–41 . July 2004 . 15242733 . 10.1016/j.yjmcc.2004.04.008 .
4. Gendreau S, Voswinkel S, Torres-Salazar D, Lang N, Heidtmann H, Detro-Dassen S, Schmalzing G, Hidalgo P, Fahlke C . A trimeric quaternary structure is conserved in bacterial and human glutamate transporters . The Journal of Biological Chemistry . 279 . 38 . 39505–12 . September 2004 . 15265858 . 10.1074/jbc.M408038200 . 16077315 . free .
5. Kanai Y, Hediger MA . The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects . Pflügers Archiv . 447 . 5 . 469–79 . February 2004 . 14530974 . 10.1007/s00424-003-1146-4 . 21564906 .
6. Danbolt NC . Glutamate uptake . Progress in Neurobiology . 65 . 1 . 1–105 . September 2001 . 11369436 . 10.1016/S0301-0082(00)00067-8 . 27347413 .
7. Storck T, Schulte S, Hofmann K, Stoffel W . Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain . Proceedings of the National Academy of Sciences of the United States of America . 89 . 22 . 10955–9 . November 1992 . 1279699 . 50461 . 10.1073/pnas.89.22.10955 . 1992PNAS...8910955S . free .
8. Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, Nash N, Kuncl RW . Localization of neuronal and glial glutamate transporters . Neuron . 13 . 3 . 713–25 . September 1994 . 7917301 . 10.1016/0896-6273(94)90038-8 . 45299639 . free .
9. Rauen T, Taylor WR, Kuhlbrodt K, Wiessner M . High-affinity glutamate transporters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in transmitter clearance . Cell and Tissue Research . 291 . 1 . 19–31 . January 1998 . 9394040 . 10.1007/s004410050976 . 6814592 .
10. Jen JC, Wan J, Palos TP, Howard BD, Baloh RW . Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures . Neurology . 65 . 4 . 529–34 . August 2005 . 16116111 . 10.1212/01.WNL.0000172638.58172.5a . 22492395 .
11. Mason DJ, Brakspear K, Wilson C, Williams R, Kotwal RS . Expression of glutamate receptors and transporters in human subchondral bone in osteoarthritis . Orthopaedic Proceedings . July 2010 . 93-B . SUPP_I . 411 . 10.1302/0301-620X.93BSUPP_I.0930069b . The British Editorial Society of Bone & Joint Surgery . 31 January 2024 .
12. Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T . DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters . Molecular Pharmacology . 53 . 2 . 195–201 . February 1998 . 9463476 . 10.1124/mol.53.2.195.
13. Jensen AA, Erichsen MN, Nielsen CW, Stensbøl TB, Kehler J, Bunch L . Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1 . Journal of Medicinal Chemistry . 52 . 4 . 912–5 . February 2009 . 19161278 . 10.1021/jm8013458 .