Amino Acids

, Volume 45, Issue 1, pp 133–142 | Cite as

Neuroprotective properties of the excitatory amino acid carrier 1 (EAAC1)

  • Koji Aoyama
  • Toshio NakakiEmail author
Minireview Article


Extracellular glutamate should be maintained at low levels to conserve optimal neurotransmission and prevent glutamate neurotoxicity in the brain. Excitatory amino acid transporters (EAATs) play a pivotal role in removing extracellular glutamate in the central nervous system (CNS). Excitatory amino acid carrier 1 (EAAC1) is a high-affinity Na+-dependent neuronal EAAT that is ubiquitously expressed in the brain. However, most glutamate released in the synapses is cleared by glial EAATs, but not by EAAC1 in vivo. In the CNS, EAAC1 is widely distributed in somata and dendrites but not in synaptic terminals. The contribution of EAAC1 to the control of extracellular glutamate levels seems to be negligible in the brain. However, EAAC1 can transport not only extracellular glutamate but also cysteine into the neurons. Cysteine is an important substrate for glutathione (GSH) synthesis in the brain. GSH has a variety of neuroprotective functions, while its depletion induces neurodegeneration. Therefore, EAAC1 might exert a critical role for neuroprotection in neuronal GSH metabolism rather than glutamatergic neurotransmission, while EAAC1 dysfunction would cause neurodegeneration. Despite the potential importance of EAAC1 in the brain, previous studies have mainly focused on the glutamate neurotoxicity induced by glial EAAT dysfunction. In recent years, however, several studies have revealed regulatory mechanisms of EAAC1 functions in the brain. This review will summarize the latest information on the EAAC1-regulated neuroprotective functions in the CNS.


Glutathione Cysteine uptake EAAC1 GTRAP3-18 Neurodegeneration 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abdul-Ghani M, Gougeon PY, Prosser DC, Da-Silva LF, Ngsee JK (2001) PRA isoforms are targeted to distinct membrane compartments. J Biol Chem 276:6225–6233CrossRefPubMedGoogle Scholar
  2. Akiduki S, Ikemoto MJ (2008) Modulation of the neural glutamate transporter EAAC1 by the addicsin-interacting protein ARL6IP1. J Biol Chem 283:31323–31332CrossRefPubMedGoogle Scholar
  3. Almilaji A, Pakladok T, Guo A, Munoz C, Foller M, Lang F (2012) Regulation of the glutamate transporter EAAT3 by mammalian target of rapamycin mTOR. Biochem Biophys Res Commun 421:159–163CrossRefPubMedGoogle Scholar
  4. Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Chen Y, Swanson RA (2006) Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci 9:119–126CrossRefPubMedGoogle Scholar
  5. Aoyama K, Watabe M, Nakaki T (2008) Regulation of neuronal glutathione synthesis. J Pharmacol Sci 108:227–238CrossRefPubMedGoogle Scholar
  6. Aoyama K, Wang F, Matsumura N, Kiyonari H, Shioi G, Tanaka K, Kinoshita C, Kikuchi-Utsumi K, Watabe M, Nakaki T (2012a) Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice. Neurobiol Dis 45:973–982CrossRefPubMedGoogle Scholar
  7. Aoyama K, Watabe M, Nakaki T (2012b) Modulation of neuronal glutathione synthesis by EAAC1 and its interacting protein GTRAP3-18. Amino Acids 42:163–169CrossRefPubMedGoogle Scholar
  8. Arriza JL, Eliasof S, Kavanaugh MP, Amara SG (1997) Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc Natl Acad Sci USA 94:4155–4160CrossRefPubMedGoogle Scholar
  9. Berman AE, Chan WY, Brennan AM, Reyes RC, Adler BL, Suh SW, Kauppinen TM, Edling Y, Swanson RA (2011) N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1-/- mouse. Ann Neurol 69:509–520CrossRefPubMedGoogle Scholar
  10. Bigdeli MR, Hajizadeh S, Froozandeh M, Heidarianpour A, Rasoulian B, Asgari AR, Pourkhalili K, Khoshbaten A (2008) Normobaric hyperoxia induces ischemic tolerance and upregulation of glutamate transporters in the rat brain and serum TNF-alpha level. Exp Neurol 212:298–306CrossRefPubMedGoogle Scholar
  11. Bigdeli MR, Rahnema M, Khoshbaten A (2009) Preconditioning with sublethal ischemia or intermittent normobaric hyperoxia up-regulates glutamate transporters and tumor necrosis factor-alpha converting enzyme in the rat brain. J Stroke Cerebrovasc Dis 18:336–342CrossRefPubMedGoogle Scholar
  12. Burger PM, Mehl E, Cameron PL, Maycox PR, Baumert M, Lottspeich F, De Camilli P, Jahn R (1989) Synaptic vesicles immunoisolated from rat cerebral cortex contain high levels of glutamate. Neuron 3:715–720CrossRefPubMedGoogle Scholar
  13. Cadenas E, Davies KJ (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med 29:222–230CrossRefPubMedGoogle Scholar
  14. Cao L, Li L, Zuo Z (2012) N-acetylcysteine reverses existing cognitive impairment and increased oxidative stress in glutamate transporter type 3 deficient mice. Neuroscience 220:85–89CrossRefPubMedGoogle Scholar
  15. Cassano T, Serviddio G, Gaetani S, Romano A, Dipasquale P, Cianci S, Bellanti F, Laconca L, Romano AD, Padalino I, LaFerla FM, Nicoletti F, Cuomo V, Vendemiale G (2012) Glutamatergic alterations and mitochondrial impairment in a murine model of Alzheimer disease. Neurobiol Aging 33:1121.e1–e12CrossRefGoogle Scholar
  16. Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527–605PubMedGoogle Scholar
  17. Chen YA, Scheller RH (2001) SNARE-mediated membrane fusion. Nat Rev Mol Cell Biol 2:98–106CrossRefPubMedGoogle Scholar
  18. Chen Y, Swanson RA (2003) Astrocytes and brain injury. J Cereb Blood Flow Metab 23:137–149CrossRefPubMedGoogle Scholar
  19. Cherian L, Goodman JC, Robertson CS (2000) Brain nitric oxide changes after controlled cortical impact injury in rats. J Neurophysiol 83:2171–2178PubMedGoogle Scholar
  20. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634CrossRefPubMedGoogle Scholar
  21. Clements JD (1996) Transmitter timecourse in the synaptic cleft: its role in central synaptic function. Trends Neurosci 19:163–171CrossRefPubMedGoogle Scholar
  22. Clements JD, Lester RA, Tong G, Jahr CE, Westbrook GL (1992) The time course of glutamate in the synaptic cleft. Science 258:1498–1501CrossRefPubMedGoogle Scholar
  23. Coco S, Verderio C, Trotti D, Rothstein JD, Volterra A, Matteoli M (1997) Non-synaptic localization of the glutamate transporter EAAC1 in cultured hippocampal neurons. Eur J Neurosci 9:1902–1910CrossRefPubMedGoogle Scholar
  24. Commandeur JN, Stijntjes GJ, Vermeulen NP (1995) Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role in bioactivation and detoxication mechanisms of xenobiotics. Pharmacol Rev 47:271–330PubMedGoogle Scholar
  25. Cooper AJ, Kristal BS (1997) Multiple roles of glutathione in the central nervous system. Biol Chem 378:793–802PubMedGoogle Scholar
  26. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695CrossRefPubMedGoogle Scholar
  27. Crino PB, Jin H, Shumate MD, Robinson MB, Coulter DA, Brooks-Kayal AR (2002) Increased expression of the neuronal glutamate transporter (EAAT3/EAAC1) in hippocampal and neocortical epilepsy. Epilepsia 43:211–218CrossRefPubMedGoogle Scholar
  28. Daikhin Y, Yudkoff M (2000) Compartmentation of brain glutamate metabolism in neurons and glia. J Nutr 130:1026S–1031SPubMedGoogle Scholar
  29. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105CrossRefPubMedGoogle Scholar
  30. Davis KE, Straff DJ, Weinstein EA, Bannerman PG, Correale DM, Rothstein JD, Robinson MB (1998) 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 18:2475–2485PubMedGoogle Scholar
  31. Diamond JS, Jahr CE (1997) Transporters buffer synaptically released glutamate on a submillisecond time scale. J Neurosci 17:4672–4687PubMedGoogle Scholar
  32. Doi T, Ueda Y, Nagatomo K, Willmore LJ (2009) Role of glutamate and GABA transporters in development of pentylenetetrazol-kindling. Neurochem Res 34:1324–1331CrossRefPubMedGoogle Scholar
  33. Douen AG, Akiyama K, Hogan MJ, Wang F, Dong L, Chow AK, Hakim A (2000) Preconditioning with cortical spreading depression decreases intraischemic cerebral glutamate levels and down-regulates excitatory amino acid transporters EAAT1 and EAAT2 from rat cerebal cortex plasma membranes. J Neurochem 75:812–818CrossRefPubMedGoogle Scholar
  34. Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62:649–671CrossRefPubMedGoogle Scholar
  35. Dringen R, Pfeiffer B, Hamprecht B (1999) Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J Neurosci 19:562–569PubMedGoogle Scholar
  36. Duerson K, Woltjer RL, Mookherjee P, Leverenz JB, Montine TJ, Bird TD, Pow DV, Rauen T, Cook DG (2009) Detergent-insoluble EAAC1/EAAT3 aberrantly accumulates in hippocampal neurons of Alzheimer’s disease patients. Brain Pathol 19:267–278CrossRefPubMedGoogle Scholar
  37. During MJ, Spencer DD (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341:1607–1610CrossRefPubMedGoogle Scholar
  38. Escartin C, Won SJ, Malgorn C, Auregan G, Berman AE, Chen PC, Deglon N, Johnson JA, Suh SW, Swanson RA (2011) Nuclear factor erythroid 2-related factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino acid transporter 3 expression. J Neurosci 31:7392–7401CrossRefPubMedGoogle Scholar
  39. Fairman WA, Vandenberg RJ, Arriza JL, Kavanaugh MP, Amara SG (1995) An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375:599–603CrossRefPubMedGoogle Scholar
  40. Fonnum F (1984) Glutamate: a neurotransmitter in mammalian brain. J Neurochem 42:1–11CrossRefPubMedGoogle Scholar
  41. Fournier KM, Robinson MB (2006) A dominant-negative variant of SNAP-23 decreases the cell surface expression of the neuronal glutamate transporter EAAC1 by slowing constitutive delivery. Neurochem Int 48:596–603CrossRefPubMedGoogle Scholar
  42. Fournier KM, Gonzalez MI, Robinson MB (2004) Rapid trafficking of the neuronal glutamate transporter, EAAC1: evidence for distinct trafficking pathways differentially regulated by protein kinase C and platelet-derived growth factor. J Biol Chem 279:34505–34513CrossRefPubMedGoogle Scholar
  43. Fray AE, Ince PG, Banner SJ, Milton ID, Usher PA, Cookson MR, Shaw PJ (1998) The expression of the glial glutamate transporter protein EAAT2 in motor neuron disease: an immunohistochemical study. Eur J Neurosci 10:2481–2489CrossRefPubMedGoogle Scholar
  44. Furuta A, Rothstein JD, Martin LJ (1997) Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J Neurosci 17:8363–8375PubMedGoogle Scholar
  45. Garnier P, Ying W, Swanson RA (2003) Ischemic preconditioning by caspase cleavage of poly(ADP-ribose) polymerase-1. J Neurosci 23:7967–7973PubMedGoogle Scholar
  46. Gonzalez MI, Kazanietz MG, Robinson MB (2002) Regulation of the neuronal glutamate transporter excitatory amino acid carrier-1 (EAAC1) by different protein kinase C subtypes. Mol Pharmacol 62:901–910CrossRefPubMedGoogle Scholar
  47. Gonzalez MI, Krizman-Genda E, Robinson MB (2007a) Caveolin-1 regulates the delivery and endocytosis of the glutamate transporter, excitatory amino acid carrier 1. J Biol Chem 282:29855–29865CrossRefPubMedGoogle Scholar
  48. Gonzalez MI, Susarla BT, Fournier KM, Sheldon AL, Robinson MB (2007b) Constitutive endocytosis and recycling of the neuronal glutamate transporter, excitatory amino acid carrier 1. J Neurochem 103:1917–1931CrossRefPubMedGoogle Scholar
  49. Grewer C, Rauen T (2005) Electrogenic glutamate transporters in the CNS: molecular mechanism, pre-steady-state kinetics, and their impact on synaptic signaling. J Membr Biol 203:1–20CrossRefPubMedGoogle Scholar
  50. Had-Aissouni L (2012a) Toward a new role for plasma membrane sodium-dependent glutamate transporters of astrocytes: maintenance of antioxidant defenses beyond extracellular glutamate clearance. Amino Acids 42:181–197CrossRefPubMedGoogle Scholar
  51. Had-Aissouni L (2012b) Maintenance of antioxidant defenses of brain cells: plasma membrane glutamate transporters and beyond. Amino Acids 42:159–161CrossRefPubMedGoogle Scholar
  52. Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59:1609–1623CrossRefPubMedGoogle Scholar
  53. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945CrossRefPubMedGoogle Scholar
  54. Head BP, Insel PA (2007) Do caveolins regulate cells by actions outside of caveolae? Trends Cell Biol 17:51–57CrossRefPubMedGoogle Scholar
  55. Himi T, Ikeda M, Yasuhara T, Nishida M, Morita I (2003) Role of neuronal glutamate transporter in the cysteine uptake and intracellular glutathione levels in cultured cortical neurons. J Neural Transm 110:1337–1348CrossRefPubMedGoogle Scholar
  56. 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 (2012) The density of EAAC1 (EAAT3) glutamate transporters expressed by neurons in the mammalian CNS. J Neurosci 32:6000–6013CrossRefPubMedGoogle Scholar
  57. Hosseinzadeh Z, Bhavsar SK, Sopjani M, Alesutan I, Saxena A, Dermaku-Sopjani M, Lang F (2011) Regulation of the glutamate transporters by JAK2. Cell Physiol Biochem 28:693–702CrossRefPubMedGoogle Scholar
  58. Huang Y, Feng X, Sando JJ, Zuo Z (2006) Critical role of serine 465 in isoflurane-induced increase of cell-surface redistribution and activity of glutamate transporter type 3. J Biol Chem 281:38133–38138CrossRefPubMedGoogle Scholar
  59. Ikonen E (2001) Roles of lipid rafts in membrane transport. Curr Opin Cell Biol 13:470–477CrossRefPubMedGoogle Scholar
  60. Imada K, Leonard WJ (2000) The Jak-STAT pathway. Mol Immunol 37:1–11CrossRefPubMedGoogle Scholar
  61. Jang BG, Won SJ, Kim JH, Choi BY, Lee MW, Sohn M, Song HK, Suh SW (2012) EAAC1 gene deletion alters zinc homeostasis and enhances cortical neuronal injury after transient cerebral ischemia in mice. J Trace Elem Med Biol 26:85–88CrossRefPubMedGoogle Scholar
  62. Jenner P (1994) Oxidative damage in neurodegenerative disease. Lancet 344:796–798CrossRefPubMedGoogle Scholar
  63. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(Suppl 3):S26–S36 discussion S36–S28CrossRefPubMedGoogle Scholar
  64. Kanai Y, Hediger MA (1992) Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360:467–471CrossRefPubMedGoogle Scholar
  65. Kanai Y, Bhide PG, DiFiglia M, Hediger MA (1995) Neuronal high-affinity glutamate transport in the rat central nervous system. Neuroreport 6:2357–2362CrossRefPubMedGoogle Scholar
  66. Kato H, Kogure K, Araki T, Itoyama Y (1994) Astroglial and microglial reactions in the gerbil hippocampus with induced ischemic tolerance. Brain Res 664:69–76CrossRefPubMedGoogle Scholar
  67. Kirino T (2002) Ischemic tolerance. J Cereb Blood Flow Metab 22:1283–1296CrossRefPubMedGoogle Scholar
  68. Kondo K, Hashimoto H, Kitanaka J, Sawada M, Suzumura A, Marunouchi T, Baba A (1995) Expression of glutamate transporters in cultured glial cells. Neurosci Lett 188:140–142CrossRefPubMedGoogle Scholar
  69. Krizman-Genda E, Gonzalez MI, Zelenaia O, Robinson MB (2005) Evidence that Akt mediates platelet-derived growth factor-dependent increases in activity and surface expression of the neuronal glutamate transporter, EAAC1. Neuropharmacology 49:872–882CrossRefPubMedGoogle Scholar
  70. Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A, Volsky DJ, Fisher PB (2008) Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. J Biol Chem 283:13116–13123CrossRefPubMedGoogle Scholar
  71. Lee S, Park SH, Zuo Z (2012) Effects of isoflurane on learning and memory functions of wild-type and glutamate transporter type 3 knockout mice. J Pharm Pharmacol 64:302–307CrossRefPubMedGoogle Scholar
  72. Lehmann A, Hagberg H, Orwar O, Sandberg M (1993) Cysteine sulphinate and cysteate: mediators of cysteine toxicity in the neonatal rat brain? Eur J Neurosci 5:1398–1412CrossRefPubMedGoogle Scholar
  73. Li X, Valencia A, Sapp E, Masso N, Alexander J, Reeves P, Kegel KB, Aronin N, Difiglia M (2010) Aberrant Rab11-dependent trafficking of the neuronal glutamate transporter EAAC1 causes oxidative stress and cell death in Huntington’s disease. J Neurosci 30:4552–4561CrossRefPubMedGoogle Scholar
  74. Lin CI, Orlov I, Ruggiero AM, Dykes-Hoberg M, Lee A, Jackson M, Rothstein JD (2001) Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18. Nature 410:84–88CrossRefPubMedGoogle Scholar
  75. Liu Y, Vidensky S, Ruggiero AM, Maier S, Sitte HH, Rothstein JD (2008) Reticulon RTN2B regulates trafficking and function of neuronal glutamate transporter EAAC1. J Biol Chem 283:6561–6571CrossRefPubMedGoogle Scholar
  76. Lu Z, Zhang W, Zhang N, Jiang J, Luo Q, Qiu Y (2008) The expression of glutamate transporters in chest compression-induced audiogenic epilepsy: a comparative study. Neurol Res 30:915–919CrossRefPubMedGoogle Scholar
  77. Ma K, Zheng S, Zuo Z (2006) The transcription factor regulatory factor X1 increases the expression of neuronal glutamate transporter type 3. J Biol Chem 281:21250–21255CrossRefPubMedGoogle Scholar
  78. Maier S, Reiterer V, Ruggiero AM, Rothstein JD, Thomas S, Dahm R, Sitte HH, Farhan H (2009) GTRAP3-18 serves as a negative regulator of Rab1 in protein transport and neuronal differentiation. J Cell Mol Med 13:114–124CrossRefPubMedGoogle Scholar
  79. Malinski T, Bailey F, Zhang ZG, Chopp M (1993) Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 13:355–358CrossRefPubMedGoogle Scholar
  80. Mandal PK, Tripathi M, Sugunan S (2012) Brain oxidative stress: detection and mapping of anti-oxidant marker ‘Glutathione’ in different brain regions of healthy male/female, MCI and Alzheimer patients using non-invasive magnetic resonance spectroscopy. Biochem Biophys Res Commun 417:43–48CrossRefPubMedGoogle Scholar
  81. Marini A, Novelli A (1991) DL-threo-3-hydroxyaspartate reduces NMDA receptor activation by glutamate in cultured neurons. Eur J Pharmacol 194:131–132CrossRefPubMedGoogle Scholar
  82. Mathern GW, Mendoza D, Lozada A, Pretorius JK, Dehnes Y, Danbolt NC, Nelson N, Leite JP, Chimelli L, Born DE, Sakamoto AC, Assirati JA, Fried I, Peacock WJ, Ojemann GA, Adelson PD (1999) Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology 52:453–472CrossRefPubMedGoogle Scholar
  83. Meldrum BS (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 130:1007S–1015SPubMedGoogle Scholar
  84. Milton ID, Banner SJ, Ince PG, Piggott NH, Fray AE, Thatcher N, Horne CH, Shaw PJ (1997) Expression of the glial glutamate transporter EAAT2 in the human CNS: an immunohistochemical study. Brain Res Mol Brain Res 52:17–31CrossRefPubMedGoogle Scholar
  85. Molteni R, Ying Z, Gomez-Pinilla F (2002) Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarray. Eur J Neurosci 16:1107–1116CrossRefPubMedGoogle Scholar
  86. Nafia I, Re DB, Masmejean F, Melon C, Kachidian P, Kerkerian-Le Goff L, Nieoullon A, Had-Aissouni L (2008) Preferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunction. J Neurochem 105:484–496CrossRefPubMedGoogle Scholar
  87. Nandagopal K, Dawson TM, Dawson VL (2001) Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. J Pharmacol Exp Ther 297:474–478PubMedGoogle Scholar
  88. Olanow CW, Tatton WG (1999) Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci 22:123–144CrossRefPubMedGoogle Scholar
  89. Olney JW, de Gubareff T (1978) Glutamate neurotoxicity and Huntington’s chorea. Nature 271:557–559CrossRefPubMedGoogle Scholar
  90. Olney JW, Ho OL (1970) Brain damage in infant mice following oral intake of glutamate, aspartate or cysteine. Nature 227:609–611CrossRefPubMedGoogle Scholar
  91. Olney JW, Ho OL, Rhee V, Schainker B (1972) Cysteine-induced brain damage in infant and fetal rodents. Brain Res 45:309–313CrossRefPubMedGoogle Scholar
  92. Olney JW, Zorumski C, Price MT, Labruyere J (1990) L-cysteine, a bicarbonate-sensitive endogenous excitotoxin. Science 248:596–599CrossRefPubMedGoogle Scholar
  93. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424CrossRefPubMedGoogle Scholar
  94. Peghini P, Janzen J, Stoffel W (1997) Glutamate transporter EAAC-1-deficient mice develop dicarboxylic aminoaciduria and behavioral abnormalities but no neurodegeneration. EMBO J 16:3822–3832CrossRefPubMedGoogle Scholar
  95. Perry TL, Hansen S (1990) What excitotoxin kills striatal neurons in Huntington’s disease? Clues from neurochemical studies. Neurology 40:20–24CrossRefPubMedGoogle Scholar
  96. Persson M, Ronnback L (2012) Microglial self-defence mediated through GLT-1 and glutathione. Amino Acids 42:207–219CrossRefPubMedGoogle Scholar
  97. Phillis JW, Ren J, O’Regan MH (2000) Transporter reversal as a mechanism of glutamate release from the ischemic rat cerebral cortex: studies with DL-threo-beta-benzyloxyaspartate. Brain Res 868:105–112CrossRefPubMedGoogle Scholar
  98. Pines G, Danbolt NC, Bjoras M, Zhang Y, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J, Seeberg E, Kanner BI (1992) Cloning and expression of a rat brain L-glutamate transporter. Nature 360:464–467CrossRefPubMedGoogle Scholar
  99. Plaitakis A, Shashidharan P (2000) Glutamate transport and metabolism in dopaminergic neurons of substantia nigra: implications for the pathogenesis of Parkinson’s disease. J Neurol 247(Suppl 2):II25–II35CrossRefPubMedGoogle Scholar
  100. Pomara N, Singh R, Deptula D, Chou JC, Schwartz MB, LeWitt PA (1992) Glutamate and other CSF amino acids in Alzheimer’s disease. Am J Psychiatry 149:251–254PubMedGoogle Scholar
  101. Proper EA, Hoogland G, Kappen SM, Jansen GH, Rensen MG, Schrama LH, van Veelen CW, van Rijen PC, van Nieuwenhuizen O, Gispen WH, de Graan PN (2002) Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125:32–43CrossRefPubMedGoogle Scholar
  102. Rakhade SN, Loeb JA (2008) Focal reduction of neuronal glutamate transporters in human neocortical epilepsy. Epilepsia 49:226–236CrossRefPubMedGoogle Scholar
  103. Rao VL, Dogan A, Todd KG, Bowen KK, Kim BT, Rothstein JD, Dempsey RJ (2001) Antisense knockdown of the glial glutamate transporter GLT-1, but not the neuronal glutamate transporter EAAC1, exacerbates transient focal cerebral ischemia-induced neuronal damage in rat brain. J Neurosci 21:1876–1883PubMedGoogle Scholar
  104. Rexhepaj R, Grahammer F, Volkl H, Remy C, Wagner CA, Sandulache D, Artunc F, Henke G, Nammi S, Capasso G, Alessi DR, Lang F (2006) Reduced intestinal and renal amino acid transport in PDK1 hypomorphic mice. FASEB J 20:2214–2222CrossRefPubMedGoogle Scholar
  105. Rosenberg PA, Aizenman E (1989) Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci Lett 103:162–168CrossRefPubMedGoogle Scholar
  106. Ross JR, Porter BE, Buckley PT, Eberwine JH, Robinson MB (2011) mRNA for the EAAC1 subtype of glutamate transporter is present in neuronal dendrites in vitro and dramatically increases in vivo after a seizure. Neurochem Int 58:366–375CrossRefPubMedGoogle Scholar
  107. Rossi DJ, Oshima T, Attwell D (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403:316–321CrossRefPubMedGoogle Scholar
  108. Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326:1464–1468CrossRefPubMedGoogle Scholar
  109. 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 13:713–725CrossRefPubMedGoogle Scholar
  110. Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38:73–84CrossRefPubMedGoogle Scholar
  111. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686CrossRefPubMedGoogle Scholar
  112. 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 (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77CrossRefPubMedGoogle Scholar
  113. Ruggiero AM, Liu Y, Vidensky S, Maier S, Jung E, Farhan H, Robinson MB, Sitte HH, Rothstein JD (2008) The endoplasmic reticulum exit of glutamate transporter is regulated by the inducible mammalian Yip6b/GTRAP3-18 protein. J Biol Chem 283:6175–6183CrossRefPubMedGoogle Scholar
  114. Sas K, Robotka H, Toldi J, Vecsei L (2007) Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. J Neurol Sci 257:221–239CrossRefPubMedGoogle Scholar
  115. Schafer FQ, Buettner GR (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 30:1191–1212CrossRefPubMedGoogle Scholar
  116. Schniepp R, Kohler K, Ladewig T, Guenther E, Henke G, Palmada M, Boehmer C, Rothstein JD, Broer S, Lang F (2004) Retinal colocalization and in vitro interaction of the glutamate transporter EAAT3 and the serum- and glucocorticoid-inducible kinase SGK1 [correction]. Invest Ophthalmol Vis Sci 45:1442–1449CrossRefPubMedGoogle Scholar
  117. Shanker G, Allen JW, Mutkus LA, Aschner M (2001) The uptake of cysteine in cultured primary astrocytes and neurons. Brain Res 902:156–163CrossRefPubMedGoogle Scholar
  118. Shashidharan P, Huntley GW, Murray JM, Buku A, Moran T, Walsh MJ, Morrison JH, Plaitakis A (1997) Immunohistochemical localization of the neuron-specific glutamate transporter EAAC1 (EAAT3) in rat brain and spinal cord revealed by a novel monoclonal antibody. Brain Res 773:139–148CrossRefPubMedGoogle Scholar
  119. Sheldon AL, Gonzalez MI, Robinson MB (2006) A carboxyl-terminal determinant of the neuronal glutamate transporter, EAAC1, is required for platelet-derived growth factor-dependent trafficking. J Biol Chem 281:4876–4886CrossRefPubMedGoogle Scholar
  120. Shupliakov O, Brodin L, Cullheim S, Ottersen OP, Storm-Mathisen J (1992) Immunogold quantification of glutamate in two types of excitatory synapse with different firing patterns. J Neurosci 12:3789–3803PubMedGoogle Scholar
  121. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD (1994) Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 36:348–355CrossRefPubMedGoogle Scholar
  122. Simantov R, Crispino M, Hoe W, Broutman G, Tocco G, Rothstein JD, Baudry M (1999) Changes in expression of neuronal and glial glutamate transporters in rat hippocampus following kainate-induced seizure activity. Brain Res Mol Brain Res 65:112–123CrossRefPubMedGoogle Scholar
  123. Sims KD, Straff DJ, Robinson MB (2000) Platelet-derived growth factor rapidly increases activity and cell surface expression of the EAAC1 subtype of glutamate transporter through activation of phosphatidylinositol 3-kinase. J Biol Chem 275:5228–5237CrossRefPubMedGoogle Scholar
  124. Sopjani M, Alesutan I, Dermaku-Sopjani M, Fraser S, Kemp BE, Foller M, Lang F (2010) Down-regulation of Na+-coupled glutamate transporter EAAT3 and EAAT4 by AMP-activated protein kinase. J Neurochem 113:1426–1435PubMedGoogle Scholar
  125. 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 USA 89:10955–10959CrossRefPubMedGoogle Scholar
  126. Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA (2007) Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J Clin Invest 117:910–918CrossRefPubMedGoogle Scholar
  127. Szabo C, Ischiropoulos H, Radi R (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 6:662–680CrossRefPubMedGoogle Scholar
  128. 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 (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699–1702CrossRefPubMedGoogle Scholar
  129. Tower DB, Young OM (1973) The activities of butyrylcholinesterase and carbonic anhydrase, the rate of anaerobic glycolysis, and the question of a constant density of glial cells in cerebral cortices of various mammalian species from mouse to whale. J Neurochem 20:269–278CrossRefPubMedGoogle Scholar
  130. Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100:328–341CrossRefPubMedGoogle Scholar
  131. Trendelenburg G, Dirnagl U (2005) Neuroprotective role of astrocytes in cerebral ischemia: focus on ischemic preconditioning. Glia 50:307–320CrossRefPubMedGoogle Scholar
  132. Trotti D, Rossi D, Gjesdal O, Levy LM, Racagni G, Danbolt NC, Volterra A (1996) Peroxynitrite inhibits glutamate transporter subtypes. J Biol Chem 271:5976–5979CrossRefPubMedGoogle Scholar
  133. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344CrossRefPubMedGoogle Scholar
  134. 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 (1998) Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice. Eur J Neurosci 10:976–988CrossRefPubMedGoogle Scholar
  135. Won SJ, Yoo BH, Brennan AM, Shin BS, Kauppinen TM, Berman AE, Swanson RA, Suh SW (2010) EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia. J Neurosci 30:15409–15418CrossRefPubMedGoogle Scholar
  136. Xia P, Pei G, Schwarz W (2006) Regulation of the glutamate transporter EAAC1 by expression and activation of delta-opioid receptor. Eur J Neurosci 24:87–93CrossRefPubMedGoogle Scholar
  137. Zerangue N, Kavanaugh MP (1996a) Interaction of L-cysteine with a human excitatory amino acid transporter. J Physiol 493(Pt 2):419–423PubMedGoogle Scholar
  138. Zerangue N, Kavanaugh MP (1996b) Flux coupling in a neuronal glutamate transporter. Nature 383:634–637CrossRefPubMedGoogle Scholar

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© Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Department of PharmacologyTeikyo University School of MedicineItabashiJapan

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