Mechanisms of glutamate transport

Physiological Reviews

Volumn 93, Issue 4, 2013, Pages 1621-1657

  Vandenberg, Robert J ^a   Ryan, Renae M ^a  

^a UNIVERSITY OF SYDNEY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATASE (POTASSIUM SODIUM); EXCITATORY AMINO ACID TRANSPORTER; EXCITATORY AMINO ACID TRANSPORTER 1; EXCITATORY AMINO ACID TRANSPORTER 2; EXCITATORY AMINO ACID TRANSPORTER 3; EXCITATORY AMINO ACID TRANSPORTER 4; EXCITATORY AMINO ACID TRANSPORTER 5; GLUTAMATE TRANSPORTER; GLUTAMIC ACID; PROTEIN KINASE C;

ASTROCYTE; BRAIN REGION; CENTRAL NERVOUS SYSTEM; CEREBELLUM; CHLORIDE CONDUCTANCE; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; CRYSTALLIZATION; HUMAN; MAMMAL; MOLECULAR MODEL; NEUROLOGIC DISEASE; NEUROTRANSMITTER UPTAKE; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROKARYOTE; PROTEIN EXPRESSION; PROTEIN FAMILY; REVIEW; SIGNAL TRANSDUCTION;

AMINO ACID SEQUENCE; ANIMALS; BIOLOGICAL TRANSPORT; CENTRAL NERVOUS SYSTEM; GLUTAMATE PLASMA MEMBRANE TRANSPORT PROTEINS; GLUTAMATES; HUMANS; MOLECULAR SEQUENCE DATA; SIGNAL TRANSDUCTION; VESICULAR GLUTAMATE TRANSPORT PROTEINS;

EID: 84885820366     PISSN: 00319333     EISSN: 15221210     Source Type: Journal    
DOI: 10.1152/physrev.00007.2013     Document Type: Review

References (309)

1. Abrahamsen B, Schneider N, Erichsen MN, Huynh TH, Fahlke C, Bunch L, Jensen AA. Allosteric modulation of an excitatory amino acid transporter: the subtype-selective inhibitor UCPH-101 exerts sustained inhibition of EAAT1 through an intramonomeric site in the trimerization domain. J Neurosci 33: 1068-1087, 2013.
2. Allen NJ, Karadottir R, Attwell D. Reversal or reduction of glutamate and GABA transport in CNS pathology and therapy. Pflügers Arch 449: 132-142, 2004.
3. Andreini C, Bertini I, Cavallaro G. Minimal functional sites allow a classification of zinc sites in proteins. PloS One 6: e26325, 2011.
4. Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Chen Y, Swanson RA. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci 9: 119-126, 2006.
5. Arnold PD, Sicard T, Burroughs E, Richter MA, Kennedy JL. Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arch Gen Psychiatry 63: 769-776, 2006.
6. Arriza JL, Eliasof S, Kavanaugh MP, Amara SG. Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc Natl Acad Sci USA 94: 4155-4160, 1997.
7. Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG. Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci 14: 5559-5569, 1994.
8. Arriza JL, Kavanaugh MP, Fairman WA, Wu YN, Murdoch GH, North RA, Amara SG. Cloning and expression of a human neutral amino acid transporter with structural similarity to the glutamate transporter gene family. J Biol Chem 268: 15329-15332, 1993.
9. Attwell D, Mobbs P. Neurotransmitter transporters. Curr Opin Neurobiol 4: 353-359, 1994.
10. Auger C, Attwell D. Fast removal of synaptic glutamate by postsynaptic transporters. Neuron 28: 547-558, 2000.
11. Auray-Blais C, Cyr D, Drouin R. Quebec neonatal mass urinary screening programme: from micromolecules to macromolecules. J Inherit Metab Dis 30: 515-521, 2007.
12. Bailey CG, Ryan RM, Thoeng AD, Ng C, King K, Vanslambrouck JM, Auray-Blais C, Vandenberg RJ, Broer S, Rasko JE. Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. J Clin Invest 121: 446-453, 2011.
13. Balcar VJ, Johnston GA. The structural specificity of the high affinity uptake of L-glutamate and L-aspartate by rat brain slices. J Neurochem 19: 2657-2666, 1972.
14. Barbour B, Szatkowski M, Ingledew N, Attwell D. Arachidonic acid induces a prolonged inhibition of glutamate uptake into glial cells. Nature 342: 918-920, 1989.
15. + Site in the aspartate transporter GltPh and the human glutamate transporter, EAAT1. PLoS One DOI:101371/journal pone.0033058: 2012.
16. Bauer DE, Jackson JG, Genda EN, Montoya MM, Yudkoff M, Robinson MB. The glutamate transporter, GLAST, participates in a macromolecular complex that supports glutamate metabolism. Neurochem Int 61: 566-574, 2012.
17. Beart PM, O'Shea RD. Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol 150: 5-17, 2007.
18. Beckstrom H, Julsrud L, Haugeto O, Dewar D, Graham DI, Lehre KP, Storm-Mathisen J, Danbolt NC. Interindividual differences in the levels of the glutamate transporters GLAST and GLT, but no clear correlation with Alzheimer's disease. J Neurosci Res 55: 218-229, 1999.
19. Beller JA, Gurkoff GG, Berman RF, Lyeth BG. Pharmacological enhancement of glutamate transport reduces excitotoxicity in vitro. Restorative Neurol Neurosci 29: 331-346, 2011.
20. Bendahan A, Armon A, Madani N, Kavanaugh MP, Kanner BI. Arginine 447 plays a pivotal role in substrate interactions in a neuronal glutamate transporter. J Biol Chem 275: 37436-37442, 2000.
21. Berger UV, Hediger MA. Distribution of the glutamate transporters GLAST and GLT-1 in rat circumventricular organs, meninges, and dorsal root ganglia. J Comp Neurol 421: 385-399, 2000.
22. Bergles DE, Tzingounis AV, Jahr CE. Comparison of coupled and uncoupled currents during glutamate uptake by GLT-1 transporters. J Neurosci 22: 10153-10162, 2002.
23. Billups B, Rossi D, Attwell D. Anion conductance behavior of the glutamate uptake carrier in salamander retinal glial cells. J Neurosci 16: 6722-6731, 1996.
24. Binns BC, Huang Y, Goettl VM, Hackshaw KV, Stephens RL Jr. Glutamate uptake is attenuated in spinal deep dorsal and ventral horn in the rat spinal nerve ligation model. Brain Res 1041: 38-47, 2005.
25. Borre L, Kanner BI. Coupled, but not uncoupled, fluxes in a neuronal glutamate transporter can be activated by lithium ions. J Biol Chem 276: 40396-40401, 2001.
26. Boudker O, Ryan RM, Yernool D, Shimamoto K, Gouaux E. Coupling substrate and ion binding to extracellular gate of a sodium-dependent aspartate transporter. Nature 445: 387-393, 2007.
27. Boudker O, Verdon G. Structural perspectives on secondary active transporters. Trends Pharmacol Sci 31: 418-426.
28. Bouvier M, Szatkowski M, Amato A, Attwell D. The glial cell glutamate uptake carrier countertransports pH-changing anions. Nature 360: 471-474, 1992.
29. Bridges RJ, Esslinger CS. The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes. Pharmacol Ther 107: 271-285, 2005.
30. Bridges RJ, Kavanaugh MP, Chamberlin AR. A pharmacological review of competitive inhibitors and substrates of high-affinity, sodium-dependent glutamate transport in the central nervous system. Curr Pharm Des 5: 363-379, 1999.
31. Bridges RJ, Natale NR, Patel SA. System xc(-) cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol 165: 20-34, 2012.
32. Bridges RJ, Stanley MS, Anderson MW, Cotman CW, Chamberlin AR. Conformationally defined neurotransmitter analogues. Selective inhibition of glutamate uptake by one pyrrolidine-2, 4-dicarboxylate diastereomer. J Med Chem 34: 717-725, 1991.
33. Brocke L, Bendahan A, Grunewald M, Kanner BI. Proximity of two oppositely oriented reentrant loops in the glutamate transporter GLT-1 identified by paired cysteine mutagenesis. J Biol Chem 277: 3985-3992, 2002.
34. Broer S. Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev 88: 249-286, 2008.
35. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18: 327-338, 1997.
36. Bull ND, Barnett NL. Antagonists of protein kinase C inhibit rat retinal glutamate transport activity in situ. J Neurochem 81: 472-480, 2002.
37. Butchbach ME, Tian G, Guo H, Lin CL. Association of excitatory amino acid transporters, especially EAAT2, with cholesterol-rich lipid raft microdomains: importance for excitatory amino acid transporter localization and function. J Biol Chem 279: 34388-34396, 2004.
38. Callender R, Gameiro A, Pinto A, De Micheli C, Grewer C. Mechanism of inhibition of the glutamate transporter EAAC1 by the conformationally constrained glutamate analogue (-)-HIP-B. Biochemistry 51: 5486-5495, 2012.
39. Canolle B, Masmejean F, Melon C, Nieoullon A, Pisano P, Lortet S. Glial soluble factors regulate the activity and expression of the neuronal glutamate transporter EAAC1: implication of cholesterol. J Neurochem 88: 1521-1532, 2004.
40. Casado M, Bendahan A, Zafra F, Danbolt NC, Aragon C, Gimenez C, Kanner BI. Phosphorylation and modulation of brain glutamate transporters by protein kinase C. J Biol Chem 268: 27313-27317, 1993.
41. Clements JD, Lester RA, Tong G, Jahr CE, Westbrook GL. The time course of glutamate in the synaptic cleft. Science 258: 1498-1501, 1992.
42. Colton CK, Kong Q, Lai L, Zhu MX, Seyb KI, Cuny GD, Xian J, Glicksman MA, Lin CL. Identification of translational activators of glial glutamate transporter EAAT2 through cell-based high-throughput screening: an approach to prevent excitotoxicity. J Biomol Screening 15: 653-662, 2010.
43. Compton EL, Taylor EM, Mindell JA. The 3-4 loop of an archaeal glutamate transporter homolog experiences ligand-induced structural changes and is essential for transport. Proc Natl Acad Sci USA 107: 12840-12845, 2010.
44. +-dependent glutamate transporter GLAST-1 by site-directed mutagenesis. J Biol Chem 270: 25207-25212, 1995.
45. Conradt M, Stoffel W. Inhibition of the high-affinity brain glutamate transporter GLAST-1 via direct phosphorylation. J Neurochem 68: 1244-1251, 1997.
46. Conti F, DeBiasi S, Minelli A, Rothstein JD, Melone M. EAAC1, a high-affinity glutamate tranporter, is localized to astrocytes and gabaergic neurons besides pyramidal cells in the rat cerebral cortex. Cerebral Cortex 8: 108-116, 1998.
47. Crisman TJ, Qu S, Kanner BI, Forrest LR. Inward-facing conformation of glutamate transporters as revealed by their inverted-topology structural repeats. Proc Natl Acad Sci USA 106: 20752-20757, 2009.
48. 3H]aspartate binding in cerebral cortex in patients with Alzheimer's and Parkinson's diseases. Neurosci Lett 79: 213-217, 1987.
49. Danbolt NC. Glutamate uptake. Prog Neurobiol 65: 1-105, 2001.
50. Davis KE, Straff DJ, Weinstein EA, Bannerman PG, Correale DM, Rothstein JD, Robinson MB. Multiple signaling pathways regulate cell surface expression and activity of the excitatory amino acid carrier 1 subtype of Glu transporter in C6 glioma. J Neurosci 18: 2475-2485, 1998.
51. De Vries B, Mamsa H, Stam AH, Wan J, Bakker SL, Vanmolkot KR, Haan J, Terwindt GM, Boon EM, Howard BD, Frants RR, Baloh RW, Ferrari MD, Jen JC, van den Maagdenberg AM. Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake. Arch Neurol 66: 97-101, 2009.
52. DeChancie J, Shrivastava IH, Bahar I. The mechanism of substrate release by the aspartate transporter GltPh: insights from simulations. Mol Biosystems 7: 832-842, 2011.
53. Dehnes Y, Chaudhry FA, Ullensvang K, Lehre KP, Storm-Mathisen J, Danbolt NC. The glutamate transporter EAAT4 in rat cerebellar Purkinje cells: a glutamate-gated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia. J Neurosci 18: 3606-3619, 1998.
54. Diamond JS, Jahr CE. Synaptically released glutamate does not overwhelm transporters on hippocampal astrocytes during high-frequency stimulation. J Neurophysiol 83: 2835-2843, 2000.
55. Diamond JS, Jahr CE. Transporters buffer synaptically released glutamate on a submillisecond time scale. J Neurosci 17: 4672-4687, 1997.
56. Dickel DE, Veenstra-VanderWeele J, Cox NJ, Wu X, Fischer DJ, Van Etten-Lee M, Himle JA, Leventhal BL, Cook EH Jr, Hanna GL. Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Arch Gen Psychiatry 63: 778-785, 2006.
57. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev 51: 7-61, 1999.
58. Divito CB, Amara SG. Close encounters of the oily kind: regulation of transporters by lipids. Mol Interventions 9: 252-262, 2009.
59. Doble A. The pharmacology and mechanism of action of riluzole. Neurology 47: S233-241, 1996.
60. Duan S, Anderson CM, Stein BA, Swanson RA. Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. J Neurosci 19: 10193-10200, 1999.
61. Dunlop J. Glutamate-based therapeutic approaches: targeting the glutamate transport system. Curr Opin Pharmacol 6: 103-107, 2006.
62. Dunlop J, Eliasof S, Stack G, McIlvain HB, Greenfield A, Kowal D, Petroski R, Carrick TW. AY855 (3-amino-tricyclo[2.2.1.02.6]heptane-1, 3-dicarboxylicacid): a novel, EAAT2-preferring, nonsubstrate inhibitor of high-affinity glutamate uptake. Br J Pharmacol 140: 839-846, 2003.
63. Dunlop J, McIlvain HB, Carrick TA, Jow B, Lu Q, Kowal D, Lin S, Greenfield A, Grosanu C, Fan K, Petroski R, Williams J, Foster A, Butera J. Characterization of novel aryl-ether, biaryl, and fluorene aspartic acid and diaminopropionic acid analogs as potent inhibitors of the high-affinity glutamate transporter EAAT2. Mol Pharmacol 68: 974-982, 2005.
64. El Mestikawy S, Wallen-Mackenzie A, Fortin GM, Descarries L, Trudeau LE. From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nature Rev Neurosci 12: 204-216, 2011.
65. Eliasof S, McIlvain HB, Petroski RE, Foster AC, Dunlop J. Pharmacological characterization of threo-3-methylglutamic acid with excitatory amino acid transporters in native and recombinant systems. J Neurochem 77: 550-557, 2001.
66. Erecinska M, Wantorsky D, Wilson DF. Aspartate transport in synaptosomes from rat brain. J Biol Chem 258: 9069-9077, 1983.
67. Erichsen MN, Huynh TH, Abrahamsen B, Bastlund JF, Bundgaard C, Monrad O, Bekker-Jensen A, Nielsen CW, Frydenvang K, Jensen AA, Bunch L. Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5, 6, 7, 8-tetrahydro-4H-chrom ene-3-carbonitrile (UCPH-101). J Med Chem 53: 7180-7191, 2010.
68. Eskandari S, Kreman M, Kavanaugh MP, Wright EM, Zampighi GA. Pentameric assembly of a neuronal glutamate transporter. Proc Natl Acad Sci USA 97: 8641-8646, 2000.
69. Fairman WA, Sonders MS, Murdoch GH, Amara SG. Arachidonic acid elicits a substrate-gated proton current associated with the glutamate transporter EAAT4. Nat Neurosci 1: 105-113, 1998.
70. Fairman WA, Vandenberg RJ, Arriza JL, Kavanaugh MP, Amara SG. An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375: 599-603, 1995.
71. Fontana AC, de Oliveira Beleboni R, Wojewodzic MW, Ferreira Dos Santos W, Coutinho-Netto J, Grutle NJ, Watts SD, Danbolt NC, Amara SG. Enhancing glutamate transport: mechanism of action of Parawixin1, a neuroprotective compound from Parawixia bistriata spider venom. Mol Pharmacol 72: 1228-1237, 2007.
72. Fontana AC, Guizzo R, de Oliveira Beleboni R, Meirelles ESAR, Coimbra NC, Amara SG, dos Santos WF, Coutinho-Netto J. Purification of a neuroprotective component of Parawixia bistriata spider venom that enhances glutamate uptake. Br J Pharmacol 139: 1297-1309, 2003.
73. Francis PT. Glutamatergic systems in Alzheimer's disease. Int J Geriatr Psychiatry 18: S15-21, 2003.
74. Francis PT. Pyramidal neurone modulation: a therapeutic target for Alzheimer's disease. Neurodegeneration 5: 461-465, 1996.
75. Frederickson CJ. Neurobiology of zinc and zinc-containing neurons. Int Rev Neurobiol 31: 145-238, 1989.
76. Fremeau RT Jr, Voglmaier S, Seal RP, Edwards RH. VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci 27: 98-103, 2004.
77. Fumagalli E, Funicello M, Rauen T, Gobbi M, Mennini T. Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol 578: 171-176, 2008.
78. 3H]D-aspartate release by 3-hydroxy-4, 5, 6, 6a-tetrahydro-3aH-pyrrolo[3, 4-d]isoxazole-4-carboxylic acid and 3-hydroxy-4, 5, 6, 6a-tetrahydro-3aH-pyrrolo[3, 4-d]isoxazole-6-carboxylic acid, two conformationally constrained aspartate and glutamate analogs. Mol Pharmacol 66: 522-529, 2004.
79. Furness DN, Dehnes Y, Akhtar AQ, Rossi DJ, Hamann M, Grutle NJ, Gundersen V, Holmseth S, Lehre KP, Ullensvang K, Wojewodzic M, Zhou Y, Attwell D, Danbolt NC. A quantitative assessment of glutamate uptake into hippocampal synaptic terminals and astrocytes: new insights into a neuronal role for excitatory amino acid transporter 2 (EAAT2). Neuroscience 157: 80-94, 2008.
80. Furness DN, Lehre KP. Immunocytochemical localization of a high-affinity glutamateaspartate transporter, GLAST, in the rat and guinea-pig cochlea. Eur J Neurosci 9: 1961-1969, 1997.
81. Gameiro A, Braams S, Rauen T, Grewer C. The discovery of slowness: low-capacity transport and slow anion channel gating by the glutamate transporter EAAT5. Biophys J 100: 2623-2632, 2011.
82. Ganel R, Crosson CE. Modulation of human glutamate transporter activity by phorbol ester. J Neurochem 70: 993-1000, 1998.
83. Gebhardt C, Korner R, Heinemann U. Delayed anoxic depolarizations in hippocampal neurons of mice lacking the excitatory amino acid carrier 1. J Cereb Blood Flow Metab 22: 569-575, 2002.
84. Gebhardt FM, Mitrovic AD, Gilbert DF, Vandenberg RJ, Lynch JW, Dodd PR. Exonskipping splice variants of excitatory amino acid transporter-2 (EAAT2) form heteromeric complexes with full-length EAAT2. J Biol Chem 285: 31313-31324, 2010.
85. Genda EN, Jackson JG, Sheldon AL, Locke SF, Greco TM, O'Donnell JC, Spruce LA, Xiao R, Guo W, Putt M, Seeholzer S, Ischiropoulos H, Robinson MB. Co-compartmentalization of the astroglial glutamate transporter, GLT-1, with glycolytic enzymes and mitochondria. J Neurosci 31: 18275-18288, 2011.
86. 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. J Biol Chem 279: 39505-39512, 2004.
87. Ghosh M, Yang Y, Rothstein JD, Robinson MB. Nuclear factor-kappaB contributes to neuron-dependent induction of glutamate transporter-1 expression in astrocytes. J Neurosci 31: 9159-9169, 2011.
88. Gonzalez MI, Kazanietz MG, Robinson MB. Regulation of the neuronal glutamate transporter excitatory amino acid carrier-1 (EAAC1) by different protein kinase C subtypes. Mol Pharmacol 62: 901-910, 2002.
89. +-dependent high affinity glutamate/ aspartate transporter in cultured Bergmann glia by phorbol esters. J Neurosci Res 50: 585-590, 1997.
90. Gonzalez MI, Robinson MB. Neurotransmitter transporters: why dance with so many partners? Curr Opin Pharmacol 4: 30-35, 2004.
91. Gottlieb M, Domercq M, Matute C. Altered expression of the glutamate transporter EAAC1 in neurons and immature oligodendrocytes after transient forebrain ischemia. J Cereb Blood Flow Metab 20: 678-687, 2000.
92. Grazioso G, Limongelli V, Branduardi D, Novellino E, De Micheli C, Cavalli A, Parrinello M. Investigating the mechanism of substrate uptake and release in the glutamate transporter homologue Glt(Ph) through metadynamics simulations. J Am Chem Soc 134: 453-463, 2012.
93. Greenfield A, Grosanu C, Dunlop J, McIlvain B, Carrick T, Jow B, Lu Q, Kowal D, Williams J, Butera J. Synthesis and biological activities of aryl-ether-, biaryl-, and fluorene-aspartic acid and diaminopropionic acid analogs as potent inhibitors of the highaffinity glutamate transporter EAAT-2. Bioorg Med Chem Lett 15: 4985-4988, 2005.
94. Grewer C, Balani P, Weidenfeller C, Bartusel T, Tao Z, Rauen T. Individual subunits of the glutamate transporter EAAC1 homotrimer function independently of each other. Biochemistry 44: 11913-11923, 2005.
95. Grewer C, Watzke N, Rauen T, Bicho A. Is the glutamate residue Glu-373 the proton acceptor of the excitatory amino acid carrier 1? J Biol Chem 278: 2585-2592, 2003.
96. Grewer C, Watzke N, Wiessner M, Rauen T. Glutamate translocation of the neuronal glutamate transporter EAAC1 occurs within milliseconds. Proc Natl Acad Sci USA 97: 9706-9711, 2000.
97. Griffiths R, Dunlop J, Gorman A, Senior J, Grieve A. L-Trans-pyrrolidine-2, 4-dicarboxylate and cis-1-aminocyclobutane-1, 3-dicarboxylate behave as transportable, competitive inhibitors of the high-affinity glutamate transporters. Biochem Pharmacol 47: 267-274, 1994.
98. +:aspartate coupling stoichiometry in the glutamate transporter homologue Glt(Ph). Biochemistry 49: 3511-3513, 2010.
99. Groeneveld M, Slotboom DJ. Rigidity of the subunit interfaces of the trimeric glutamate transporter GltT during translocation. J Mol Biol 372: 565-570, 2007.
100. Grunewald M, Bendahan A, Kanner BI. Biotinylation of single cysteine mutants of the glutamate transporter GLT-1 from rat brain reveals its unusual topology. Neuron 21: 623-632, 1998.
101. Grunewald M, Kanner B. Conformational changes monitored on the glutamate transporter GLT-1 indicate the existence of two neurotransmitter-bound states. J Biol Chem 270: 17017-17024, 1995.
102. Grunewald M, Kanner BI. The accessibility of a novel reentrant loop of the glutamate transporter GLT-1 is restricted by its substrate. J Biol Chem 275: 9684-9689, 2000.
103. Grunewald M, Menaker D, Kanner BI. Cysteine-scanning mutagenesis reveals a conformationally sensitive reentrant pore-loop in the glutamate transporter GLT-1. J Biol Chem 277: 26074-26080, 2002.
104. Hanna GL, Veenstra-VanderWeele J, Cox NJ, Boehnke M, Himle JA, Curtis GC, Leventhal BL, Cook EH Jr. Genome-wide linkage analysis of families with obsessivecompulsive disorder ascertained through pediatric probands. Am J Med Genet 114: 541-552, 2002.
105. Hansen PR. [Ischemic heart disease simulating congestive cardiomyopathy]. Ugeskr Laeger 147: 4212-4213, 1985.
106. Hardy J, Cowburn R, Barton A, Reynolds G, Lofdahl E, O'Carroll AM, Wester P, Winblad B. Region-specific loss of glutamate innervation in Alzheimer's disease. Neurosci Lett 73: 77-80, 1987.
107. Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron 75: 762-777, 2012.
108. Hassel B, Brathe A. Neuronal pyruvate carboxylation supports formation of transmitter glutamate. J Neurosci 20: 1342-1347, 2000.
109. Haugeto O, Ullensvang K, Levy LM, Chaudhry FA, Honore T, Nielsen M, Lehre KP, Danbolt NC. Brain glutamate transporter proteins form homomultimers. J Biol Chem 271: 27715-27722, 1996.
110. Heinzelmann G, Bastug T, Kuyucak S. Free energy simulations of ligand binding to the aspartate transporter Glt(Ph). Biophys J 101: 2380-2388, 2011.
111. Herman MA, Jahr CE. Extracellular glutamate concentration in hippocampal slice. J Neurosci 27: 9736-9741, 2007.
112. Holley DC, Kavanaugh MP. Interactions of alkali cations with glutamate transporters. Philos Trans R Soc Lond B Biol Sci 364: 155-161, 2009.
113. Holmseth S, Dehnes Y, Huang YH, Follin-Arbelet VV, Grutle NJ, Mylonakou MN, Plachez C, Zhou Y, Furness DN, Bergles DE, Lehre KP, Danbolt NC. The density of EAAC1 (EAAT3) glutamate transporters expressed by neurons in the mammalian CNS. J Neurosci 32: 6000-6013, 2012.
114. Holmseth S, Scott HA, Real K, Lehre KP, Leergaard TB, Bjaalie JG, Danbolt NC. The concentrations and distributions of three C-terminal variants of the GLT1 (EAAT2; slc1a2) glutamate transporter protein in rat brain tissue suggest differential regulation. Neuroscience 162: 1055-1071, 2009.
115. Honig LS, Chambliss DD, Bigio EH, Carroll SL, Elliott JL. Glutamate transporter EAAT2 splice variants occur not only in ALS, but also inADand controls. Neurology 55: 1082-1088, 2000.
116. Hotzy J, Machtens JP, Fahlke C. Neutralizing aspartate 83 modifies substrate translocation of excitatory amino acid transporter 3 (EAAT3) glutamate transporters. J Biol Chem 287: 20016-20026, 2012.
117. Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, DeGennaro LJ, Cleveland DW, Rothstein JD. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA 99: 1604-1609, 2002.
118. Huang S, Ryan RM, Vandenberg RJ. The role of cation binding in determining substrate selectivity of glutamate transporters. J Biol Chem 284: 4510-4515, 2009.
119. Huang S, Vandenberg RJ. Mutations in transmembrane domains 5 and 7 of the human excitatory amino acid transporter 1 affect the substrate-activated anion channel. Biochemistry 46: 9685-9692, 2007.
120. Huang Z, Tajkhorshid E. Dynamics of the extracellular gate and ion-substrate coupling in the glutamate transporter. Biophys J 95: 2292-2300, 2008.
121. + site and the sequence of extracellular binding events in the glutamate transporter. Biophys J 99: 1416-1425, 2010.
122. +-dependent glutamate transporter GLAST-1 is expressed in bone and a splice variant of this molecule is expressed in bone and brain. FEBS Lett 485: 13-18, 2000.
123. + antiporter and insights into mechanism of action and regulation by pH. Nature 435: 1197-1202, 2005.
124. Huynh TH, Shim I, Bohr H, Abrahamsen B, Nielsen B, Jensen AA, Bunch L. Structureactivity relationship study of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5, 6, 7, 8-tetrahydro-4H-chrom ene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio Hartree-Fock calculations. J Med Chem 55: 5403-5412, 2012.
125. Iwasaki Y, Ikeda K, Kinoshita M. Plasma amino acid levels in patients with amyotrophic lateral sclerosis. J Neurol Sci 107: 219-222, 1992.
126. Jackson M, Song W, Liu MY, Jin L, Dykes-Hoberg M, Lin CI, Bowers WJ, Federoff HJ, Sternweis PC, Rothstein JD. Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature 410: 89-93, 2001.
127. Jacob CP, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N, Ravid R, Roggendorf W, Riederer P, Grunblatt E. Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer's disease. J Alzheimer's Dis 11: 97-116, 2007.
128. Jardetzky O. Simple allosteric model for membrane pumps. Nature 211: 969-970, 1966.
129. Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 130: 2484-2493, 2007.
130. Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 65: 529-534, 2005.
131. Jensen AA, Erichsen MN, Nielsen CW, Stensbol TB, Kehler J, Bunch L. Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1. J Med Chem 52: 912-915, 2009.
132. Jiang J, Amara SG. New views of glutamate transporter structure and function: advances and challenges. Neuropharmacology 60: 172-181, 2011.
133. Jiang J, Shrivastava IH, Watts SD, Bahar I, Amara SG. Large collective motions regulate the functional properties of glutamate transporter trimers. Proc Natl Acad Sci USA 108: 15141-15146, 2011.
134. Johnston GA, Kennedy SM, Twitchin B. Action of the neurotoxin kainic acid on high affinity uptake of L-glutamic acid in rat brain slices. J Neurochem 32: 121-127, 1979.
135. Kalandadze A, Wu Y, Robinson MB. Protein kinase C activation decreases cell surface expression of the GLT-1 subtype of glutamate transporter. Requirement of a carboxyl-terminal domain and partial dependence on serine 486. J Biol Chem 277: 45741-45750, 2002.
136. Kanai Y, Hediger MA. Primary structure and functional characterization of a highaffinity glutamate transporter. Nature 360: 467-471, 1992.
137. Kang TC, Hwang IK, Park SK, An SJ, Yoon DK, Moon SM, Lee YB, Sohn HS, Cho SS, Won MH. Chronological changes of N-methyl-D-aspartate receptors and excitatory amino acid carrier 1 immunoreactivities in CA1 area and subiculum after transient forebrain ischemia. J Neurocytol 30: 945-955, 2001.
138. Kavanaugh MP, Bendahan A, Zerangue N, Zhang Y, Kanner BI. Mutation of an amino acid residue influencing potassium coupling in the glutamate transporter GLT-1 induces obligate exchange. J Biol Chem 272: 1703-1708, 1997.
139. Ketheeswaranathan P, Turner NA, Spary EJ, Batten TF, McColl BW, Saha S. Changes in glutamate transporter expression in mouse forebrain areas following focal ischemia. Brain Res 1418: 93-103, 2011.
140. Kiryk A, Aida T, Tanaka K, Banerjee P, Wilczynski GM, Meyza K, Knapska E, Filipkowski RK, Kaczmarck L, Danysz W. Behaviorial characterization of GLT1 (+/-) mice as a model of mild glutamatergic hyperfunction. Neurotox Res 13: 19-30, 2008.
141. Koch HP, Brown RL, Larsson HP. The glutamate-activated anion conductance in excitatory amino acid transporters is gated independently by the individual subunits. J Neurosci 27: 2943-2947, 2007.
142. Koch HP, Hubbard JM, Larsson HP. Voltage-independent sodium-binding events reported by the 4B-4C loop in the human glutamate transporter excitatory amino acid transporter 3. J Biol Chem 282: 24547-24553, 2007.
143. 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. Mol Pharmacol 56: 1095-1104, 1999.
144. Kovermann P, Machtens JP, Ewers D, Fahlke C. A conserved aspartate determines pore properties of anion channels associated with excitatory amino acid transporter 4 (EAAT4). J Biol Chem 285: 23676-23686, 2010.
145. Kugler P, Schmitt A. Glutamate transporter EAAC1 is expressed in neurons and glial cells in the rat nervous system. Glia 27: 129-142, 1999.
146. Kwon JS, Joo YH, Nam HJ, Lim M, Cho EY, Jung MH, Choi JS, Kim B, Kang DH, Oh S, Park T, Hong KS. Association of the glutamate transporter gene SLC1A1 with atypical antipsychotics-induced obsessive-compulsive symptoms. Arch Gen Psychiatry 66: 1233-1241, 2009.
147. Larsson HP, Wang X, Lev B, Baconguis I, Caplan DA, Vyleta NP, Koch HP, Diez-Sampedro A, Noskov SY. Evidence for a third sodium-binding site in glutamate transporters suggests an ion/substrate coupling model. Proc Natl Acad Sci USA 107: 13912-13917, 2010.
148. Leary GP, Holley DC, Stone EF, Lyda BR, Kalachev LV, Kavanaugh MP. The central cavity in trimeric glutamate transporters restricts ligand diffusion. Proc Natl Acad Sci USA 108: 14980-14985, 2011.
149. Leary GP, Stone EF, Holley DC, Kavanaugh MP. The glutamate and chloride permeation pathways are colocalized in individual neuronal glutamate transporter subunits. J Neurosci 27: 2938-2942, 2007.
150. Lee A, Pow DV. Astrocytes: glutamate transport and alternate splicing of transporters. Int J Biochem Cell Biol 42: 1901-1906, 2010.
151. Lee SG, Kim K, Kegelman TP, Dash R, Das SK, Choi JK, Emdad L, Howlett EL, Jeon HY, Su ZZ, Yoo BK, Sarkar D, Kim SH, Kang DC, Fisher PB. Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity. Cancer Res 71: 6514-6523, 2011.
152. Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A, Volsky DJ, Fisher PB. Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. J Biol Chem 283: 13116-13123, 2008.
153. Lehre KP, Danbolt NC. The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci 18: 8751-8757, 1998.
154. Leighton BH, Seal RP, Watts SD, Skyba MO, Amara SG. Structural rearrangements at the translocation pore of the human glutamate transporter, EAAT1. J Biol Chem 281: 29788-29796, 2006.
155. Lerma J, Herranz AS, Herreras O, Abraira V, Martin del Rio R. In vivo determination of extracellular concentration of amino acids in the rat hippocampus A method based on brain dialysis and computerized analysis. Brain Res 384: 145-155, 1986.
156. Lester RA, Clements JD, Westbrook GL, Jahr CE. Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature 346: 565-567, 1990.
157. Levy LM, Warr O, Atwell D. Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake. J Neurosci 18: 9620-9628, 1998.
158. Li S, Mallory M, Alford M, Tanaka S, Masliah E. Glutamate transporter alterations in Alzheimer disease are possibly associated with abnormal APP expression. J Neuropathol Exp Neurol 56: 901-911, 1997.
159. Li Y, Zhou Y, Danbolt NC. The rates of postmortem proteolysis of glutamate transporters differ dramatically between cells and between transporter substrates. J Histochem Cytochem 60: 811-821, 2012.
160. Liang Z, Valla J, Sefidvash-Hockley S, Rogers J, Li R. Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer's disease patients. J Neurochem 80: 807-814, 2002.
161. Liaw WJ, Stephens RL Jr, Binns BC, Chu Y, Sepkuty JP, Johns RA, Rothstein JD, Tao YX. Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 115: 60-70, 2005.
162. Lin CI, Orlov I, Ruggiero AM, Dykes-Hoberg M, Lee A, Jackson M, Rothstein JD. Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18. Nature 410: 84-88, 2001.
163. Lin CL, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD. Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20: 589-602, 1998.
164. Lipski J, Wan CK, Bai JZ, Pi R, Li D, Donnelly D. Neuroprotective potential of ceftriaxone in in vitro models of stroke. Neuroscience 146: 617-629, 2007.
165. Liu MT, Rothstein JD, Gershon MD, Kirchgessner AL. Glutamatergic enteric neurons. J Neurosci 17: 4764-4784, 1997.
166. Lopez-Colome AM, Martinez-Lozada Z, Guillem AM, Lopez E, Ortega A. Glutamate transporter-dependent mTOR phosphorylation in Muller glia cells. ASN Neuro 2012.
167. +-glutamate cotransporter expressed in Xenopus oocytes. J Physiol 542: 817-828, 2002.
168. +-coupled glutamate cotransporter expressed in Xenopus oocytes. J Physiol 530: 367-378, 2001.
169. MacAulay N, Hamann S, Zeuthen T. Water transport in the brain: role of cotransporters. Neuroscience 129: 1031-1044, 2004.
170. MacAulay N, Zeuthen T. Water transport between CNS compartments: contributions of aquaporins and cotransporters. Neuroscience 168: 941-956, 2010.
171. Maier S, Reiterer V, Ruggiero AM, Rothstein JD, Thomas S, Dahm R, Sitte HH, Farhan H. GTRAP3-18 serves as a negative regulator of Rab1 in protein transport and neuronal differentiation. J Cell Mol Med 13: 114-124, 2009.
172. Marcaggi P, Attwell D. Role of glial amino acid transporters in synaptic transmission and brain energetics. Glia 47: 217-225, 2004.
173. Martinez-Lopez I, Garcia C, Barber T, Vina JR, Miralles VJ. The L-glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2): expression and regulation in rat lactating mammary gland. Mol Membr Biol 15: 237-242, 1998.
174. Matthews JC, Beveridge MJ, Malandro MS, Rothstein JD, Campbell-Thompson M, Verlander JW, Kilberg MS, Novak DA. Activity and protein localization of multiple glutamate transporters in gestation day 14 vs. day 20 rat placenta. Am J Physiol Cell Physiol 274: C603-C614, 1998.
175. Mayer ML. Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation. Curr Opin Neurobiol 21: 283-290, 2011.
176. McKenna MC. The glutamate-glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res 85: 3347-3358, 2007.
177. Melzer N, Meuth SG, Torres-Salazar D, Bittner S, Zozulya AL, Weidenfeller C, Kotsiari A, Stangel M, Fahlke C, Wiendl H. A beta-lactam antibiotic dampens excitotoxic inflammatory CNS damage in a mouse model of multiple sclerosis. PloS One 3: e3149, 2008.
178. Menaker D, Bendahan A, Kanner BI. The substrate specificity of a neuronal glutamate transporter is determined by the nature of the coupling ion. J Neurochem 99: 20-28, 2006.
179. Meyer T, Fromm A, Munch C, Schwalenstocker B, Fray AE, Ince PG, Stamm S, Gron G, Ludolph AC, Shaw PJ. The RNA of the glutamate transporter EAAT2 is variably spliced in amyotrophic lateral sclerosis and normal individuals. J Neurol Sci 170: 45-50, 1999.
180. Mim C, Balani P, Rauen T, Grewer C. The glutamate transporter subtypes EAAT4 and EAATs 1-3 transport glutamate with dramatically different kinetics and voltage dependence but share a common uptake mechanism. J Gen Physiol 126: 571-589, 2005.
181. Mitrovic AD, Amara SG, Johnston GA, Vandenberg RJ. Identification of functional domains of the human glutamate transporters EAAT1 and EAAT2. J Biol Chem 273: 14698-14706, 1998.
182. 2+ inhibits the anion conductance of the glutamate transporter EAAT4. J Biol Chem 276: 26071-26076, 2001.
183. Morth JP, Pedersen BP, Toustrup-Jensen MS, Sorensen TL, Petersen J, Andersen JP, Vilsen B, Nissen P. Crystal structure of the sodium-potassium pump. Nature 450: 1043-1049, 2007.
184. + binding to the glutamate transporter EAAC1. ACS Chem Neurosci 3: 1073-1083, 2012.
185. Nagai M, Abe K, Okamoto K, Itoyama Y. Identification of alternative splicing forms of GLT-1 mRNAin the spinal cord of amyotrophic lateral sclerosis patients. Neurosci Lett 244: 165-168, 1998.
186. Nakayama T, Kawakami H, Tanaka K, Nakamura S. Expression of three glutamate transporter subtype mRNAs in human brain regions and peripheral tissues. Brain Res 36: 189-192, 1996.
187. Newton AC. Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev 101: 2353-2364, 2001.
188. Nordstrom EJ, Burton FH. A transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder circuitry. Mol Psychiatry 7:, 524617-625, 2002.
189. Nothmann D, Leinenweber A, Torres-Salazar D, Kovermann P, Hotzy J, Gameiro A, Grewer C, Fahlke C. Hetero-oligomerization of neuronal glutamate transporters. J Biol Chem 286: 3935-3943, 2011.
190. Nyitrai G, Kekesi KA, Juhasz G. Extracellular level of GABA and Glu: in vivo microdialysis-HPLC measurements. Curr Top Med Chem 6: 935-940, 2006.
191. Ogunrinu TA, Sontheimer H. Hypoxia increases the dependence of glioma cells on glutathione. J Biol Chem 285: 37716-37724, 2010.
192. Otis TS, Kavanaugh MP, Jahr CE. Postsynaptic glutamate transport at the climbing fiber-Purkinje cell synapse. Science 277: 1515-1518, 1997.
193. Ottersen OP, Zhang N, Walberg F. Metabolic compartmentation of glutamate and glutamine: morphological evidence obtained by quantitative immunocytochemistry in rat cerebellum. Neuroscience 46: 519-534, 1992.
194. Owe SG, Marcaggi P, Attwell D. The ionic stoichiometry of the GLAST glutamate transporter in salamander retinal glia. J Physiol 577: 591-599, 2006.
195. Peacey E, Miller CC, Dunlop J, Rattray M. The four major N-and C-terminal splice variants of the excitatory amino acid transporter GLT-1 form cell surface homomeric and heteromeric assemblies. Mol Pharmacol 75: 1062-1073, 2009.
196. Peghini P, Janzen J, Stoffel W. Glutamate transporter EAAC-1-deficient mice develop dicarboxylic aminoaciduria and behavioral abnormalities but no neurodegeneration. EMBO J 16: 3822-3832, 1997.
197. Phillips KA. The obsessive-compulsive spectrums. Psychiatr Clin N Am 25: 791-809, 2002.
198. Pines G, Danbolt NC, Bjoras M, Zhang Y, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J, Seeberg E, Kanner BI. Cloning and expression of a rat brain L-glutamate transporter. Nature 360: 464-467, 1992.
199. 1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla. Neurology 53: 71-79, 1999.
200. Plaitakis A, Caroscio JT. Abnormal glutamate metabolism in amyotrophic lateral sclerosis. Ann Neurol 22: 575-579, 1987.
201. Poulsen MV, Vandenberg RJ. Niflumic acid modulates uncoupled substrate-gated conductances in the human glutamate transporter EAAT4. J Physiol 534: 159-167, 2001.
202. Pow DV, Barnett NL. Developmental expression of excitatory amino acid transporter 5: a photoreceptor and bipolar cell glutamate transporter in rat retina. Neurosci Lett 280: 21-24, 2000.
203. Qu S, Kanner BI. Substrates and non-transportable analogues induce structural rearrangements at the extracellular entrance of the glial glutamate transporter GLT-1/ EAAT2. J Biol Chem 283: 26391-26400, 2008.
204. Rao VL, Bowen KK, Dempsey RJ. Transient focal cerebral ischemia down-regulates glutamate transporters GLT-1 and EAAC1 expression in rat brain. Neurochem Res 26: 497-502, 2001.
205. Rasmussen SA, Eisen JL. The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry 55 Suppl: 5-14, 1994.
206. Rauen T, Rothstein JD, Wassle H. Differential expression of three glutamate transporter subtypes in the rat retina. Cell Tissue Res 286: 325-336, 1996.
207. Reyes N, Ginter C, Boudker O. Transport mechanism of a bacterial homologue of glutamate transporters. Nature 462: 880-885, 2009.
208. Rose EM, Koo JC, Antflick JE, Ahmed SM, Angers S, Hampson DR. Glutamate transporter coupling to Na, K-ATPase. J Neurosci 29: 8143-8155, 2009.
209. Rosenberg DR, Keshavan MSAE. Bennett Research Award. Toward a neurodevelopmental model of of obsessive-compulsive disorder. Biol Psychiatry 43: 623-640, 1998.
210. Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ. Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J Am Acad Child Adolescent Psychiatry 39: 1096-1103, 2000.
211. Rosenberg DR, Mirza Y, Russell A, Tang J, Smith JM, Banerjee SP, Bhandari R, Rose M, Ivey J, Boyd C, Moore GJ. Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls. J Am Acad Child Adolescent Psychiatry 43: 1146-1153, 2004.
212. Rosental N, Bendahan A, Kanner BI. Multiple consequences of mutating two conserved beta-bridge forming residues in the translocation cycle of a neuronal glutamate transporter. J Biol Chem 281: 27905-27915, 2006.
213. Rosental N, Gameiro A, Grewer C, Kanner BI. A conserved aspartate residue located at the extracellular end of the binding pocket controls cation interactions in brain glutamate transporters. J Biol Chem 286: 41381-41390, 2011.
214. Rosental N, Kanner BI. A conserved methionine residue controls the substrate selectivity of a neuronal glutamate transporter. J Biol Chem 285: 21241-21248, 2010.
215. Rossi DJ, Oshima T, Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403: 316-321, 2000.
216. Rothstein JD. Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis. Adv Neurol 68: 7-27, 1995.
217. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16: 675-686, 1996.
218. 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: 713-725, 1994.
219. Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433: 73-77, 2005.
220. Rothstein JD, Tsai G, Kuncl RW, Clawson L, Cornblath DR, Drachman DB, Pestronk A, Stauch BL, Coyle JT. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 28: 18-25, 1990.
221. Ruggiero AM, Liu Y, Vidensky S, Maier S, Jung E, Farhan H, Robinson MB, Sitte HH, Rothstein JD. The endoplasmic reticulum exit of glutamate transporter is regulated by the inducible mammalian Yip6b/GTRAP3-18 protein. J Biol Chem 283: 6175-6183, 2008.
222. +-dependent aspartate transporter from Pyrococcus horikoshii. J Biol Chem 284: 17540-17548, 2009.
223. + coupling in the human glutamate transporter, EAAT1. J Neurochem 114: 565-575, 2010.
224. Ryan RM, Mindell JA. The uncoupled chloride conductance of a bacterial glutamate transporter homolog. Nat Struct Mol Biol 14: 365-371, 2007.
225. Ryan RM, Mitrovic AD, Vandenberg RJ. The chloride permeation pathway of a glutamate transporter and its proximity to the glutamate translocation pathway. J Biol Chem 279: 20742-20751, 2004.
226. Ryan RM, Vandenberg RJ. A channel in a transporter. Clin Exp Pharmacol Physiol 32: 1-6, 2005.
227. Ryan RM, Vandenberg RJ. Distinct conformational states mediate the transport and anion channel properties of the glutamate transporter EAAT-1. J Biol Chem 277: 13494-13500, 2002.
228. Schrodinger LLC. The PyMOL Molecular Graphics System, Version 1.3r1. 2010.
229. Schwartz EA, Tachibana M. Electrophysiology of glutamate and sodium co-transport in a glial cell of the salamander retina. J Physiol 426: 43-80, 1990.
230. Scott HA, Gebhardt FM, Mitrovic AD, Vandenberg RJ, Dodd PR. Glutamate transporter variants reduce glutamate uptake in Alzheimer's disease. Neurobiol Aging 32: 553e551-511, 2011.
231. Seal RP, Amara SG. A reentrant loop domain in the glutamate carrier EAAT1 participates in substrate binding and translocation. Neuron 21: 1487-1498, 1998.
232. Seal RP, Leighton BH, Amara SG. A model for the topology of excitatory amino acid transporters determined by the extracellular accessibility of substituted cysteines. Neuron 25: 695-706, 2000.
233. Seal RP, Leighton BH, Amara SG. Transmembrane topology mapping using biotincontaining sulfhydryl reagents. Methods Enzymol 296: 318-331, 1998.
234. 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. Proc Natl Acad Sci USA 98: 15324-15329, 2001.
235. +/glutamate cotransporters. J Biol Chem 268: 15351-15355, 1993.
236. Sheldon AL, Gonzalez MI, Krizman-Genda EN, Susarla BT, Robinson MB. Ubiquitination-mediated internalization and degradation of the astroglial glutamate transporter, GLT-1. Neurochem Int 53: 296-308, 2008.
237. Shigeri Y, Shimamoto K, Yasuda-Kamatani Y, Seal RP, Yumoto N, Nakajima T, Amara SG. Effects of threo-beta-hydroxyaspartate derivatives on excitatory amino acid transporters (EAAT4 and EAAT5). J Neurochem 79: 297-302, 2001.
238. Shimamoto K. Glutamate transporter blockers for elucidation of the function of excitatory neurotransmission systems. Chem Rec 8: 182-199, 2008.
239. 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. Mol Pharmacol 53: 195-201, 1998.
240. Shimamoto K, Otsubo Y, Shigeri Y, Yasuda-Kamatani Y, Satoh M, Kaneko S, Nakagawa T. Characterization of the tritium-labeled analog of L-threo-beta-benzyloxyaspartate binding to glutamate transporters. Mol Pharmacol 71: 294-302, 2007.
241. Shimamoto K, Sakai R, Takaoka K, Yumoto N, Nakajima T, Amara SG, Shigeri Y. Characterization of novel L-threo-beta-benzyloxyaspartate derivatives, potent blockers of the glutamate transporters. Mol Pharmacol 65: 1008-1015, 2004.
242. Shimamoto K, Shigeri Y, Yasuda-Kamatani Y, Lebrun B, Yumoto N, Nakajima T. Syntheses of optically pure beta-hydroxyaspartate derivatives as glutamate transporter blockers. Bioorg Med Chem Lett 10: 2407-2410, 2000.
243. Shrivastava IH, Jiang J, Amara SG, Bahar I. Time-resolved mechanism of extracellular gate opening and substrate binding in a glutamate transporter. J Biol Chem 283: 28680-28690, 2008.
244. Shugart YY, Wang Y, Samuels JF, Grados MA, Greenberg BD, Knowles JA, McCracken JT, Rauch SL, Murphy DL, Rasmussen SA, Cullen B, Hoehn-Saric R, Pinto A, Fyer AJ, Piacentini J, Pauls DL, Bienvenu OJ, Riddle MA, Liang KY, Nestadt G. A family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder in 378 families. Am J Med Genet B Neuropsychiatric Genet 150B: 886-892, 2009.
245. Slotboom DJ, Konings WN, Lolkema JS. Cysteine-scanning mutagenesis reveals a highly amphipathic, pore-lining membrane-spanning helix in the glutamate transporter GltT. J Biol Chem 276: 10775-10781, 2001.
246. Slotboom DJ, Konings WN, Lolkema JS. Structural features of the glutamate transporter family. Microbiol Mol Biol Rev 63: 293-307, 1999.
247. Slotboom DJ, Sobczak I, Konings WN, Lolkema JS. A conserved serine-rich stretch in the glutamate transporter family forms a substrate-sensitive reentrant loop. Proc Natl Acad Sci USA 96: 14282-14287, 1999.
248. Spiridon M, Kamm D, Billups B, Mobbs P, Attwell D. Modulation by zinc of the glutamate transporters in glial cells and cones isolated from the tiger salamander retina. J Physiol 506: 363-376, 1998.
249. Stewart SE, Fagerness JA, Platko J, Smoller JW, Scharf JM, Illmann C, Jenike E, Chabane N, Leboyer M, Delorme R, Jenike MA, Pauls DL. Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatric Genet 144B: 1027-1033, 2007.
250. Stolzenberg S, Khelashvili G, Weinstein H. Structural intermediates in a model of the substrate translocation path of the bacterial glutamate transporter homologue GltPh. J Physical Chem 116: 5372-5383, 2012.
251. +-dependent glutamate/aspartate transporter from rat brain. Proc Natl Acad Sci USA 89: 10955-10959, 1992.
252. Sun W, Hoffman KM, Holly DC, Kavanaugh MP. Specificity and actions of an arylaspartate inhibitor of glutamate transport at the schaffer collateral-CA1 pyramidal cell synapse. PloS One 6: 2011.
253. Sung B, Lim G, Mao J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 23: 2899-2910, 2003.
254. Susarla BT, Seal RP, Zelenaia O, Watson DJ, Wolfe JH, Amara SG, Robinson MB. Differential regulation of GLAST immunoreactivity and activity by protein kinase C: evidence for modification of amino and carboxyl termini. J Neurochem 91: 1151-1163, 2004.
255. Swarna M, Rao DN, Reddy PP. Dicarboxylic aminoaciduria associated with mental retardation. Hum Genet 82: 299-300, 1989.
256. +-dependent glutamate transporter: pharmacological characterization and lack of regulation by protein kinase C. J Pharmacol Exp Ther 289: 1600-1610, 1999.
257. Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276: 1699-1702, 1997.
258. Tao YX, Gu J, Stephens RL Jr. Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states. Mol Pain 1: 30, 2005.
259. Tao Z, Gameiro A, Grewer C. Thallium ions can replace both sodium and potassium ions in the glutamate transporter excitatory amino acid carrier 1. Biochemistry 47: 12923-12930, 2008.
260. + binding to the glutamate transporter EAAC1. J Gen Physiol 129: 331-344, 2007.
261. Tao Z, Rosental N, Kanner BI, Gameiro A, Mwaura J, Grewer C. Mechanism of cation binding to the glutamate transporter EAAC1 probed with mutation of the conserved amino acid residue Thr101. J Biol Chem 285: 17725-17733, 2010.
262. + to the glutamate-free form and cycling of the glutamate transporter EAAC1. J Biol Chem 281: 10263-10272, 2006.
263. Teichman S, Kanner BI. Aspartate-444 is essential for productive substrate interactions in a neuronal glutamate transporter. J Gen Physiol 129: 527-539, 2007.
264. Teichman S, Qu S, Kanner BI. Conserved asparagine residue located in binding pocket controls cation selectivity and substrate interactions in neuronal glutamate transporter. J Biol Chem 287: 17198-17205, 2012.
265. Teichman S, Qu S, Kanner BI. The equivalent of a thallium binding residue from an archeal homolog controls cation interactions in brain glutamate transporters. Proc Natl Acad Sci USA 106: 14297-14302, 2009.
266. Teijema HL, van Gelderen HH, Giesberts MA, Laurent de Angulo MS. Dicarboxylic aminoaciduria: an inborn error of glutamate and aspartate transport with metabolic implications, in combination with a hyperprolinemia. Metabolism 23: 115-123, 1974.
267. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62: 405-496, 2010.
268. Trotti D, Peng JB, Dunlop J, Hediger MA. Inhibition of the glutamate transporter EAAC1 expressed in Xenopus oocytes by phorbol esters. Brain Res 914: 196-203, 2001.
269. Trotti D, Rolfs A, Danbolt NC, Brown RH Jr, Hediger MA. SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat Neurosci 2: 427-433, 1999.
270. Trotti D, Volterra A, Lehre KP, Rossi D, Gjesdal O, Racagni G, Danbolt NC. Arachidonic acid inhibits a purified and reconstituted glutamate transporter directly from the water phase and not via the phospholipid membrane. J Biol Chem 270: 9890-9895, 1995.
271. Tzingounis AV, Lin CL, Rothstein JD, Kavanaugh MP. Arachidonic acid activates a proton current in the rat glutamate transporter EAAT4. J Biol Chem 273: 17315-17317, 1998.
272. Tzingounis AV, Wadiche JI. Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nature Rev Neurosci 8: 935-947, 2007.
273. +-dependent neutral amino acid transporter. J Biol Chem 271: 14883-14890, 1996.
274. Vandenberg RJ, Arriza JL, Amara SG, Kavanaugh MP. Constitutive ion fluxes and substrate binding domains of human glutamate transporters. J Biol Chem 270: 17668-17671, 1995.
275. Vandenberg RJ, Handford CA, Campbell EM, Ryan RM, Yool AJ. Water and urea permeation pathways of the human excitatory amino acid transporter EAAT1. Biochem J 439: 333-340, 2011.
276. Vandenberg RJ, Huang S, Ryan RM. Slips, leaks and channels in glutamate transporters. Channels 2: 51-58, 2008.
277. Vandenberg RJ, Ju P, Aubrey KR, Ryan RM, Mitrovic AD. Allosteric modulation of neurotransmitter transporters at excitatory synapses. Eur J Pharm Sci 23: 1-11, 2004.
278. Vandenberg RJ, Mitrovic AD, Chebib M, Balcar VJ, Johnston GA. Contrasting modes of action of methylglutamate derivatives on the excitatory amino acid transporters, EAAT1 and EAAT2. Mol Pharmacol 51: 809-815, 1997.
279. Vandenberg RJ, Mitrovic AD, Johnston GA. Molecular basis for differential inhibition of glutamate transporter subtypes by zinc ions. Mol Pharmacol 54: 189-196, 1998.
280. Vandenberg RJ, Mitrovic AD, Johnston GA. Serine-O-sulphate transport by the human glutamate transporter, EAAT2. Br J Pharmacol 123: 1593-1600, 1998.
281. Vandenberg RJ, Ryan RM. How and why are channels in transporters? Sci STKE 2005: pe17, 2005.
282. Vanhoutte N, Hermans E. Glutamate-induced glioma cell proliferation is prevented by functional expression of the glutamate transporter GLT-1. FEBS Lett 582: 1847-1852, 2008.
283. Veenstra-VanderWeele J, Xu T, Ruggiero AM, Anderson LR, Jones ST, Himle JA, Kennedy JL, Richter MA, Hanna GL, Arnold PD. Functional studies and rare variant screening of SLC1A1/EAAC1 in males with obsessive-compulsive disorder. Psychiatr Genet 22: 256-260, 2012.
284. Verdon G, Boudker O. Crystal structure of an asymmetric trimer of a bacterial glutamate transporter homolog. Nat Struct Mol Biol 2012.
285. Veruki ML, Morkve SH, Hartveit E. Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling. Nat Neurosci 9: 1388-1396, 2006.
286. Wadiche JI, Amara SG, Kavanaugh MP. Ion fluxes associated with excitatory amino acid transport. Neuron 15: 721-728, 1995.
287. Wadiche JI, Arriza JL, Amara SG, Kavanaugh MP. Kinetics of a human glutamate transporter. Neuron 14: 1019-1027, 1995.
288. Wadiche JI, Kavanaugh MP. Macroscopic and microscopic properties of a cloned glutamate transporter/chloride channel. J Neurosci 18: 7650-7661, 1998.
289. Watase K, Hashimoto K, Kano M, Yamada K, Watanabe M, Inoue Y, Okuyama S, Sakagawa T, Ogawa S, Kawashima N, Hori S, Takimoto M, Wada K, Tanaka K. Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice. Eur J Neurosci 10: 976-988, 1998.
290. Watkins S, Sontheimer H. Unique biology of gliomas: challenges and opportunities. Trends Neurosci 35: 546-556, 2012.
291. Watzke N, Bamberg E, Grewer C. Early intermediates in the transport cycle of the neuronal excitatory amino acid carrier EAAC1. J Gen Physiol 117: 547-562, 2001.
292. Watzke N, Rauen T, Bamberg E, Grewer C. On the mechanism of proton transport by the neuronal excitatory amino acid carrier 1. J Gen Physiol 116: 609-622, 2000.
293. Wendland JR, Moya PR, Timpano KR, Anavitarte AP, Kruse MR, Wheaton MG, Ren-Patterson RF, Murphy DL. A haplotype containing quantitative trait loci for SLC1A1 gene expression and its association with obsessive-compulsive disorder. Arch Gen Psychiatry 66: 408-416, 2009.
294. Wersinger E, Schwab Y, Sahel JA, Rendon A, Pow DV, Picaud S, Roux MJ. The glutamate transporter EAAT5 works as a presynaptic receptor in mouse rod bipolar cells. J Physiol 577: 221-234, 2006.
295. Willis CL, Humphrey JM, Koch HP, Hart JA, Blakely T, Ralston L, Baker CA, Shim S, Kadri M, Chamberlin AR, Bridges RJ. L-Trans-2, 3-pyrrolidine dicarboxylate: characterization of a novel excitotoxin. Neuropharmacology 35: 531-539, 1996.
296. Willour VL, Yao Shugart Y, Samuels J, Grados M, Cullen B, Bienvenu OJ, 3rd Wang Y, Liang KY, Valle D, Hoehn-Saric R, Riddle M, Nestadt G. Replication study supports evidence for linkage to 9p24 in obsessive-compulsive disorder. Am J Hum Genet 75: 508-513, 2004.
297. Winter N, Kovermann P, Fahlke C. A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents. Brain 2012.
298. Xing X, Chang LC, Kong Q, Colton CK, Lai L, Glicksman MA, Lin CL, Cuny GD. Structure-activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators. Bioorg Med Chem Lett 21: 5774-5777, 2011.
299. --dependent neurotransmitter transporters. Nature 437: 215-223, 2005.
300. Yaster M, Guan X, Petralia RS, Rothstein JD, Lu W, Tao YX. Effect of inhibition of spinal cord glutamate transporters on inflammatory pain induced by formalin and complete Freund's adjuvant. Anesthesiology 114: 412-423, 2011.
301. Yernool D, Boudker O, Jin Y, Gouaux E. Structure of a glutamate transporter homologue from Pyrococcus horikoshii. Nature 431: 811-818, 2004.
302. Yernool D, Boudker O, Folta-Stogniew E, Gouaux E. Trimeric subunit stoichiometry of the glutamate transporters from Bacillus caldotenax and Bacillus stearothermophilus. Biochemistry 42: 12981-12988, 2003.
303. Zerangue N, Arriza JL, Amara SG, Kavanaugh MP. Differential modulation of human glutamate transporter subtypes by arachidonic acid. J Biol Chem 270: 6433-6435, 1995.
304. Zerangue N, Kavanaugh MP. Flux coupling in a neuronal glutamate transporter. Nature 383: 634-637, 1996.
305. Zerangue N, Kavanaugh MP. Interaction of L-cysteine with a human excitatory amino acid transporter. J Physiol 493: 419-423, 1996.
306. +)-coupled rat brain glutamate transporter. Proc Natl Acad Sci USA 95: 751-755, 1998.
307. Zhang Y, Kanner BI. Two serine residues of the glutamate transporter GLT-1 are crucial for coupling the fluxes of sodium and the neurotransmitter. Proc Natl Acad Sci USA 96: 1710-1715, 1999.
308. Zhang Z, Tao Z, Gameiro A, Barcelona S, Braams S, Rauen T, Grewer C. Transport direction determines the kinetics of substrate transport by the glutamate transporter EAAC1. Proc Natl Acad Sci USA 104: 18025-18030, 2007.
309. Zschocke J, Allritz C, Engele J, Rein T. DNA methylation dependent silencing of the human glutamate transporter EAAT2 gene in glial cells. Glia 55: 663-674, 2007.