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Regulation and Dysregulation of Glutamate Transporters

  • Chapter
Neurotransmitter Transporters

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 175))

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Abstract

Glutamate is the primary excitatory neurotransmitter in the central nervous system. During synaptic activity, glutamate is released into the synaptic cleft and binds to glutamate receptors on the pre- and postsynaptic membrane as well as on neighboring astrocytes in order to start a number of intracellular signaling cascades. To allow for an efficient signaling to occur, glutamate levels in the synaptic cleft have to be maintained at very low levels. This process is regulated by glutamate transporters, which remove excess extracellular glutamate via a sodium-potassium coupled uptake mechanism. When extracellular glutamate levels rise to about normal, glutamate overactivates glutamate receptors, triggering a multitude of intracellular events in the postsynaptic neuron, which ultimately results in neuronal cell death. This phenomenon is known as excitotoxicity and is the underlying mechanisms of a number of neurodegenerative diseases. A dysfunction of the glutamate transporter is thought to contribute to cell death during excitotoxicity. Therefore, efforts have been made to understand the regulation of glutamate transporter function. Transporter activity can be regulated in different ways, including through gene expression, transporter protein targeting and trafficking and through posttranslational modifications of the transporter protein. The identification of these mechanisms has helped to understand the role of glutamate transporters during pathology and will aid in the development of therapeutic strategies with the transporter as a desirable target.

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References

  • 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 94:4155–4160

    PubMed  CAS  Google Scholar 

  • Barpeled O, BenHur H, Biegon A, Groner Y, Dewhurst S, Furuta A, Rothstein JD (1997) Distribution of glutamate transporter subtypes during human brain development. J Neurochem 69:2571–2580

    CAS  Google Scholar 

  • Becher A, White JH, McIlhinney RA (2001) The gamma-aminobutyric acid receptor B, but not the metabotropic glutamate receptor type-1, associates with lipid rafts in the rat cerebellum. J Neurochem 79:787–795

    PubMed  CAS  Google Scholar 

  • Behrens PF, Franz P, Woodman B, Lindenberg KS, Landwehrmeyer GB (2002) Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation. Brain 125:1908–1922

    PubMed  CAS  Google Scholar 

  • Berger UV, Hediger MA (2000) Distribution of the glutamate transporters GLAST and GLT-1 in rat circumventricular organs, meninges, and dorsal root ganglia. J Comp Neurol 421:385–399

    PubMed  CAS  Google Scholar 

  • Bruijn L, Becher M, Lee M, Anderson K, Jenkins N, Copeland N, Sisodia S, Rothstein J, Borchelt D, Price D, Cleveland D (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338

    PubMed  CAS  Google Scholar 

  • Bull ND, Barnett NL (2002) Antagonists of protein kinase C inhibit rat retinal glutamate transport activity in situ. J Neurochem 81:472–480

    PubMed  CAS  Google Scholar 

  • Butchbach ME, Tian G, Guo H, Lin CL (2004) 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

    PubMed  CAS  Google Scholar 

  • Casado M, Zafra F, Aragon C, Gimenez C (1991) Activation of high-affinity uptake of glutamate by phorbol esters in primary glial cell cultures. J Neurochem 57:1185–1190

    PubMed  CAS  Google Scholar 

  • Casado M, Bendahan A, Zafra F, Danbolt NC, Aragon C, Gimenez C, Kanner BI (1993) Phosphorylation and modulation of brain glutamate transporters by protein kinase C. J Biol Chem 268:27313–27317

    PubMed  CAS  Google Scholar 

  • Chen JC, Hsu-Chou H, Lu JL, Chiang YC, Huang HM, Wang HL, Wu T, Liao JJ, Yeh TS (2005) Down-regulation of the glial glutamate transporter GLT-1 in rat hippocampus and striatum and its modulation by a group III metabotropic glutamate receptor antagonist following transient global forebrain ischemia. Neuropharmacology 49:703–714

    PubMed  CAS  Google Scholar 

  • Chen W, Aoki C, Mahadomrongkul V, Gruber CE, Wang GJ, Blitzblau R, Irwin N, Rosenberg PA (2002) Expression of a variant form of the glutamate transporter GLT1 in neuronal cultures and in neurons and astrocytes in the rat brain. J Neurosci 22:2142–2152

    PubMed  CAS  Google Scholar 

  • Cheng C, Glover G, Banker G, Amara SG (2002) A novel sorting motif in the glutamate transporter excitatory amino acid transporter 3 directs its targeting in Madin-Darby canine kidney cells and hippocampal neurons. J Neurosci 22:10643–10652

    PubMed  CAS  Google Scholar 

  • Conradt M, Stoffel W (1997) Inhibition of the high-affinity brain glutamate transporter GLAST-1 via direct phosphorylation. J Neurochem 68:1244–1251

    PubMed  CAS  Google Scholar 

  • Conradt M, Storck T, Stoffel W (1995) Localization of N-glycosylation sites and functional role of the carbohydrate units of GLAST-1, a cloned rat brain L-glutamate/L-aspartate transporter. Eur J Biochem 229:682–687

    PubMed  CAS  Google Scholar 

  • Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    PubMed  CAS  Google Scholar 

  • 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 18:2475–2485

    PubMed  CAS  Google Scholar 

  • Derouiche A, Rauen T (1995) Coincidence of L-glutamate/L-aspartate transporter (GLAST) and glutamine synthetase (GS) immunoreactions in retinal glia: evidence for coupling of GLAST and GS in transmitter clearance. J Neurosci Res 42:131–143

    PubMed  CAS  Google Scholar 

  • Dorandeu F, Antier D, Pernot-Marino I, Lapeyre P, Lallement G (1998) Venom phospholipase A2-induced impairment of glutamate uptake: an indirect and nonselective effect related to phospholipid hydrolysis. J Neurosci Res 51:349–359

    PubMed  CAS  Google Scholar 

  • Dowd LA, Robinson MB (1996) Rapid stimulation of EAAC1-mediated Na+-dependent L-glutamate transport activity in C6 gliomacells by phorbol ester. JNeurochem 67:508–516

    CAS  Google Scholar 

  • Drejer J, Meier E, Schousboe A (1983) Novel neuron-related regulatory mechanisms for astrocytic glutamate and GABA high affinity uptake. Neurosci Lett 37:301–306

    PubMed  CAS  Google Scholar 

  • Duan S, Anderson CM, Stein BA, Swanson RA (1999) Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. J Neurosci 19:10193–10200

    PubMed  CAS  Google Scholar 

  • Eng DL, Lee YL, Lal PG (1997) Expression of glutamate uptake transporters after dibutyryl cyclic AMP differentiation and traumatic injury in cultured astrocytes. Brain Res 778:215–221

    PubMed  CAS  Google Scholar 

  • Fallon L, Moreau F, Croft BG, Labib N, Gu WJ, Fon EA (2002) Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain. J Biol Chem 277:486–491

    PubMed  CAS  Google Scholar 

  • Figiel M, Engele J (2000) Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuron-derived peptide regulating glial glutamate transport and metabolism. J Neurosci 20:3596–3605

    PubMed  CAS  Google Scholar 

  • 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 279:34505–34513

    PubMed  CAS  Google Scholar 

  • Fukamachi S, Furuta A, Ikeda T, Ikenoue T, Kaneoka T, Rothstein JD, Iwaki T (2001) Altered expressions of glutamate transporter subtypes inratmodel of neonatal cerebral hypoxiaischemia. Brain Res Dev Brain Res 132:131–139

    PubMed  CAS  Google Scholar 

  • Furness DN, Lehre KP (1997) Immunocytochemical localization of a high-affinity glutamate-aspartate transporter, GLAST, in the rat and guinea-pig cochlea. Eur J Neurosci 9:1961–1969

    PubMed  CAS  Google Scholar 

  • Furuta A, Martin LJ, Lin CL, Dykes-Hoberg M, Rothstein JD (1997a) Cellular and synaptic localization of the neuronal glutamate transporters excitatory amino acid transporter 3 and 4. Neuroscience 81:1031–1042

    PubMed  CAS  Google Scholar 

  • Furuta A, Rothstein JD, Martin LJ (1997b) Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J Neurosci 17:8363–8375

    PubMed  CAS  Google Scholar 

  • Gamboa C, Ortega A (2002) Insulin-like growth factor-1 increases activity and surface levels of the GLAST subtype of glutamate transporter. Neurochem Int 40:397–403

    PubMed  CAS  Google Scholar 

  • Gegelashvili G, Civenni G, Racagni G, Danbolt NC, Schousboe I, Schousboe A (1996) Glutamate receptor agonists up-regulate glutamate transporter GLAST in astrocytes. Neuroreport 8:261–265

    PubMed  CAS  Google Scholar 

  • Gegelashvili G, Danbolt NC, Schousboe A (1997) Neuronal soluble factors differentially regulate the expression of the GLT1 and GLAST glutamate transporters in cultured astroglia. J Neurochem 69:2612–2615

    PubMed  CAS  Google Scholar 

  • Gegelashvili G, Dehnes Y, Danbolt NC, Schousboe A (2000) The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms. Neurochem Int 37:163–170

    PubMed  CAS  Google Scholar 

  • Gegelashvili G, Robinson MB, Trotti D, Rauen T (2001) Regulation of glutamate transporters in health and disease. Prog Brain Res 132:267–286

    PubMed  CAS  Google Scholar 

  • Ginsberg SD, Martin LJ, Rothstein JD (1995) Regional deafferentation down-regulates subtypes of glutamate transporter proteins. J Neurochem 65:2800–2803

    PubMed  CAS  Google Scholar 

  • Gonzalez I, Susarla BT, Robinson MB (2005) Evidence that protein kinase Calpha interacts with and regulates the glial glutamate transporter GLT-1. J Neurochem 94:1180–1188

    PubMed  CAS  Google Scholar 

  • Gonzalez MI, Ortega A (1997) Regulation of the Na+-dependent high affinity glutamate/aspartate transporter in cultured Bergmann glia by phorbol esters. J Neurosci Res 50:585–590

    PubMed  CAS  Google Scholar 

  • Gonzalez MI, Lopez Colome AM, Ortega A (1999) Sodium-dependent glutamate transport in Muller glial cells: regulation by phorbol esters. Brain Res 831:140–145

    PubMed  CAS  Google Scholar 

  • 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 62:901–910

    PubMed  CAS  Google Scholar 

  • Gonzalez MI, Bannerman PG, Robinson MB (2003) Phorbol myristate acetate-dependent interaction of protein kinase Calpha and the neuronal glutamate transporter EAAC1. J Neurosci 23:5589–5593

    PubMed  CAS  Google Scholar 

  • Guillet BA, Velly LJ, Canolle B, Masmejean FM, Nieoullon AL, Pisano P (2005) Differential regulation by protein kinases of activity and cell surface expression of glutamate transporters in neuron-enriched cultures. Neurochem Int 46:337–346

    PubMed  CAS  Google Scholar 

  • Guo H, Lai L, Butchbach ME, Stockinger MP, Shan X, Bishop GA, Lin CL (2003) Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum Mol Genet 12:2519–2532

    PubMed  CAS  Google Scholar 

  • Hagiwara T, Tanaka K, Takai S, Maeno-Hikichi Y, Mukainaka Y, Wada K (1996) Genomic organization, promoter analysis, and chromosomal localization of the gene for the mouse glial high-affinity glutamate transporter Slc1a3. Genomics 33:508–515

    PubMed  CAS  Google Scholar 

  • Hering H, Lin CC, Sheng M (2003) Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. J Neurosci 23:3262–3271

    PubMed  CAS  Google Scholar 

  • Howland D, Liu J, She Y, Goad B, Maragakis N, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, De Gennaro L, Cleveland D, Rothstein J (2002) Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A 99:1604–1609

    PubMed  CAS  Google Scholar 

  • Ikegaya Y, Matsuura S, Ueno S, Baba A, Yamada MK, Nishiyama N, Matsuki N (2002) Betaamyloid enhances glial glutamate uptake activity and attenuates synaptic efficacy. J Biol Chem 277:32180–32186

    PubMed  CAS  Google Scholar 

  • Inage YW, Itoh M, Wada K, Takashima S (1998) Expression of two glutamate transporters, GLAST and EAAT4, in the human cerebellum: their correlation in development and neonatal hypoxic-ischemic damage. J Neuropathol Exp Neurol 57:554–562

    PubMed  CAS  Google Scholar 

  • Jackson M, Song W, Liu MY, Jin L, Dykes-Hoberg M, Lin CI, Bowers WJ, Federoff HJ, Sternweis PC, Rothstein JD (2001) Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature 410:89–93

    PubMed  CAS  Google Scholar 

  • Kalandadze A, Wu Y, Robinson MB (2002) 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

    PubMed  CAS  Google Scholar 

  • Kalandadze A, Wu Y, Fournier K, Robinson MB (2004) Identification of motifs involved in endoplasmic reticulum retention-forward trafficking of the GLT-1 subtype of glutamate transporter. J Neurosci 24:5183–5192

    PubMed  CAS  Google Scholar 

  • Kim JH, Huganir RL (1999) Organization and regulation of proteins at synapses. Curr Opin Cell Biol 11:248–254

    PubMed  CAS  Google Scholar 

  • Kim SY, Choi SY, Chao W, Volsky DJ (2003) Transcriptional regulation of human excitatory amino acid transporter 1 (EAAT1): cloning of the EAAT1 promoter and characterization of its basal and inducible activity in human astrocytes. J Neurochem 87:1485–1498

    PubMed  CAS  Google Scholar 

  • Levy LM, Lehre KP, Walaas SI, Storm-Mathisen J, Danbolt NC (1995) Down-regulation of glial glutamate transporters after glutamatergic denervation in the rat brain. Eur J Neurosci 7:2036–2041

    PubMed  CAS  Google Scholar 

  • Li S, Mallory M, Alford M, Tanaka S, Masliah E (1997) Glutamate transporter alterations in Alzheimer disease are possibly associated with abnormal APP expression. J Neuropathol Exp Neurol 56:901–911

    PubMed  CAS  Google Scholar 

  • Liang Z, Valla J, Sefidvash-Hockley S, Rogers J, Li R (2002) Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer’s disease patients. J Neurochem 80:807–814

    PubMed  Google Scholar 

  • Lievens JC, Woodman B, Mahal A, Spasic-Boscovic O, Samuel D, Kerkerian-Le Goff L, Bates GP (2001) Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis 8:807–821

    PubMed  CAS  Google Scholar 

  • Lin CL, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD (1998) Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20:589–602

    PubMed  CAS  Google Scholar 

  • Lin CLG, 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 410:84–88

    PubMed  CAS  Google Scholar 

  • Lin G, Bristol LA, Rothstein JD (1996) An abnormal mRNA leads to downregulation of glutamate transporter EAAT2 (GLT-1) expression in amyotrophic lateral sclerosis. Ann Neurol 40:540–541

    Google Scholar 

  • Linden DJ (1998) Synaptically evoked glutamate transport currents may be used to detect the expression of long-term potentiation in cerebellar culture. J Neurophysiol 79:3151–3156

    PubMed  CAS  Google Scholar 

  • Lundy DF, McBean GJ (1995) Pre-incubation of synaptosomes with arachidonic acid potentiates inhibition of [3H]D-aspartate transport. Eur J Pharmacol 291:273–279

    PubMed  CAS  Google Scholar 

  • Manzoni C, Mennini T (1997) Arachidonic acid inhibits 3H-glutamate uptake with different potencies in rodent central nervous system regions expressing different transporter subtypes. Pharmacol Res 35:149–151

    PubMed  CAS  Google Scholar 

  • Maragakis NJ, Rothstein JD (2004) Glutamate transporters: animal models to neurologic disease. Neurobiol Dis 15:461–473

    PubMed  CAS  Google Scholar 

  • Marie H, Attwell D (1999) C-terminal interactions modulate the affinity of GLAST glutamate transporters in salamander retinal glial cells. J Physiol 520:393–397

    PubMed  CAS  Google Scholar 

  • Marie H, Billups D, Bedford FK, Dumoulin A, Goyal RK, Longmore GD, Moss SJ, Attwell D (2002) The amino terminus of the glial glutamate transporter GLT-1 interacts with the LIM protein Ajuba. Mol Cell Neurosci 19:152–164

    PubMed  CAS  Google Scholar 

  • Martin LJ, Brambrink AM, Lehmann C, Portera-Cailliau C, Koehler R, Rothstein J, Traystman RJ (1997) Hypoxia-ischemia causes abnormalities in glutamate transporters and death of astroglia and neurons in newborn striatum. Ann Neurol 42:335–348

    PubMed  CAS  Google Scholar 

  • Masliah E, Alford M, Mallory M, Rockenstein E, Moechars D, Van Leuven F (2000) Abnormal glutamate transport function inmutant amyloid precursor protein transgenicmice. Exp Neurol 163:381–387

    PubMed  CAS  Google Scholar 

  • Meyer T, Speer A, Meyer B, Sitte W, Kuther G, Ludolph AC (1996) The glial glutamate transporter complementary DNA in patients with amyotrophic lateral sclerosis. Ann Neurol 40:456–459

    PubMed  CAS  Google Scholar 

  • Pawlak J, Brito V, Kuppers E, Beyer C (2005) Regulation of glutamate transporter GLAST and GLT-1 expression in astrocytes by estrogen. Brain Res Mol Brain Res 138:1–7

    PubMed  CAS  Google Scholar 

  • Raghavendra Rao VL, Rao AM, Dogan A, Bowen KK, Hatcher J, Rothstein JD, Dempsey RJ (2000) Glial glutamate transporter GLT-1 down-regulation precedes delayed neuronal death in gerbil hippocampus following transient global cerebral ischemia. Neurochem Int 36:531–537

    PubMed  CAS  Google Scholar 

  • Rao VL, Bowen KK, Dempsey RJ (2001) Transient focal cerebral ischemia down-regulates glutamate transporters GLT-1 and EAAC1 expression in rat brain. Neurochem Res 26:497–502

    PubMed  CAS  Google Scholar 

  • Rauen T (2000) Diversity of glutamate transporter expression and function in the mammalian retina. Amino Acids 19:53–62

    PubMed  CAS  Google Scholar 

  • Raunser S, Haase W, Bostina M, Parcej DN, Kuhlbrandt W (2005) High-yield expression, reconstitution and structure of the recombinant, fully functional glutamate transporter GLT-1 from Rattus norvegicus. J Mol Biol 351:598–613

    PubMed  CAS  Google Scholar 

  • 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 38:73–84

    PubMed  CAS  Google Scholar 

  • 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 amajor role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686

    PubMed  CAS  Google Scholar 

  • 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 433:73–77

    PubMed  CAS  Google Scholar 

  • Scannevin RH, Huganir RL (2000) Postsynaptic organization and regulation of excitatory synapses. Nat Rev Neurosci 1:133–141

    PubMed  CAS  Google Scholar 

  • Schlag BD, Vondrasek JR, Munir M, Kalandadze A, Zelenaia OA, Rothstein JD, Robinson MB (1998) Regulation of the glial Na+-dependent glutamate transporters by cyclic AMP analogs and neurons. Mol Pharmacol 53:355–369

    PubMed  CAS  Google Scholar 

  • Schmitt A, Asan E, Lesch KP, Kugler P (2002) A splice variant of glutamate transporter GLT1/EAAT2 expressed in neurons: cloning and localization in rat nervous system. Neuroscience 109:45–61

    PubMed  CAS  Google Scholar 

  • Shashidharan P, Plaitakis A (1993) Cloning and characterization of a glutamate transporter cDNA from human cerebellum. Biochim Biophys Acta 1216:161–164

    PubMed  CAS  Google Scholar 

  • Shashidharan P, Wittenberg I, Plaitakis A (1994) Molecular cloning of human brain glutamate/aspartate transporter II. Biochim Biophys Acta 1191:393–396

    PubMed  CAS  Google Scholar 

  • Siesjo BK, Agardh CD, Bengtsson F, Smith ML (1989) Arachidonic acid metabolism in seizures. Ann N Y Acad Sci 559:323–339

    PubMed  CAS  Google Scholar 

  • Simons K, Toomre D (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1:31–39

    PubMed  CAS  Google Scholar 

  • 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 275:5228–5237

    PubMed  CAS  Google Scholar 

  • Sitcheran R, Gupta P, Fisher PB, Baldwin AS (2005) Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression. EMBO J 24:510–520

    PubMed  CAS  Google Scholar 

  • Slotboom DJ, Konings WN, Lolkema JS (1999) Structural features of the glutamate transporter family. Microbiol Mol Biol Rev 63:293–307

    PubMed  CAS  Google Scholar 

  • Sonders MS, Quick M, Javitch JA (2005) How did the neurotransmitter cross the bilayer? A closer view. Curr Opin Neurobiol 15:296–304

    PubMed  CAS  Google Scholar 

  • Su Z, Leszczyniecka M, Kang D, Sarkar D, Chao W, Volsky D (2003) Insights into glutamate transport regulation in human astrocytes: cloning of the promoter for excitatory amino acid transporter 2 (EAAT2). Proc Natl Acad Sci U S A 100:1955–1960

    PubMed  CAS  Google Scholar 

  • Sullivan R, Rauen T, Fischer F, Wiessner M, Grewer C, Bicho A, Pow DV (2004) Cloning, transport properties, and differential localization of two splice variants of GLT-1 in the rat CNS: Implications for CNS glutamate homeostasis. Glia 45:155–169

    PubMed  Google Scholar 

  • Susarla BT, Seal RP, Zelenaia O, Watson DJ, Wolfe JH, Amara SG, Robinson MB (2004) Differential regulation of GLAST immunoreactivity and activity by protein kinase C: evidence for modification of amino and carboxyl termini. J Neurochem 91:1151–1163

    PubMed  CAS  Google Scholar 

  • Sutherland ML, Martinowich K, Rothstein JD (2001) EAAT2 overexpression plays a neuroprotective role in the SOD1 G93A model of amyotrophic lateral sclerosis. Soc Neurosci Abstr 27:607.6

    Google Scholar 

  • Suzuki T, Ito J, Takagi H, Saitoh F, Nawa H, Shimizu H (2001) Biochemical evidence for localization of AMPA-type glutamate receptor subunits in the dendritic raft. Brain Res Mol Brain Res 89:20–28

    PubMed  CAS  Google Scholar 

  • Swanson RA, Liu J, Miller JW, Rothstein JD, Farrell K, Stein BA, Longuemare MC (1997) Neuronal regulation of glutamate transporter subtype expression in astrocytes. J Neurosci 17:932–940

    PubMed  CAS  Google Scholar 

  • Tamahara S, Inaba M, Sato K, Matsuki N, Hikasa Y, Ono K (2002) Non-essential roles of cysteine residues in functional expression and redox regulatory pathways for canine glutamate/aspartate transporter based on mutagenic analysis. Biochem J 367:107–111

    PubMed  CAS  Google Scholar 

  • Tan J, Zelenaia O, Correale D, Rothstein JD, Robinson MB (1999) Expression of the GLT-1 subtype of Na+-dependent glutamate transporter: pharmacological characterization and lack of regulation by protein kinase C. J Pharmacol Exp Ther 289:1600–1610

    PubMed  CAS  Google Scholar 

  • Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699–1702

    PubMed  CAS  Google Scholar 

  • Trotti D, Nussberger S, Volterra A, Hediger MA (1997a) Differential modulation of the uptake currents by redox interconversion of cysteine residues in the human neuronal glutamate transporter EAAC1. Eur J Neurosci 9:2207–2212

    PubMed  CAS  Google Scholar 

  • Trotti D, Rizzini BL, Rossi D, Haugeto O, Racagni G, Danbolt NC, Volterra A (1997b) Neuronal and glial glutamate transporters possess an SH-based redox regulatory mechanism. Eur J Neurosci 9:1236–1243

    PubMed  CAS  Google Scholar 

  • Trotti D, Danbolt NC, Volterra A (1998) Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci 19:328–334

    PubMed  CAS  Google Scholar 

  • Trotti D, Rolfs A, Danbolt NC, Brown RH Jr, Hediger MA (1999) SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat Neurosci 2:848

    PubMed  CAS  Google Scholar 

  • Tzingounis AV, Lin CL, Rothstein JD, Kavanaugh MP (1998) Arachidonic acid activates a proton current in the rat glutamate transporter EAAT4. J Biol Chem 273:17315–17317

    PubMed  CAS  Google Scholar 

  • Vallejo-Illarramendi A, Domercq M, Matute C (2005) A novel alternative splicing form of excitatory amino acid transporter is a negative regulator of glutamate uptake. J Neurochem 95:341–348

    PubMed  CAS  Google Scholar 

  • Volterra A, Trotti D, Cassutti P, Tromba C, Salvaggio A, Melcangi RC, Racagni G (1992) High sensitivity of glutamate uptake to extracellular free arachidonic acid levels in rat cortical synaptosomes and astrocytes. J Neurochem 59:600–606

    PubMed  CAS  Google Scholar 

  • Volterra A, Trotti D, Floridi S, Racagni G (1994) Reactive oxygen species inhibit high-affinity glutamate uptake: molecular mechanism and neuropathological implications. Ann N Y Acad Sci 738:153–162

    PubMed  CAS  Google Scholar 

  • Wang Z, Li W, Mitchell CK, Carter-Dawson L (2003) Activation of protein kinase C reduces GLAST in the plasma membrane of rat Muller cells in primary culture. Vis Neurosci 20:611–619

    PubMed  Google Scholar 

  • Williams JH, Errington ML, Lynch MA, Bliss TV (1989) Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus. Nature 341:739–742

    PubMed  CAS  Google Scholar 

  • Winckler B, Mellman I (1999) Neuronal polarity: controlling the sorting and diffusion of membrane components. Neuron 23:637–640

    PubMed  CAS  Google Scholar 

  • Yamamoto Y, Gaynor RB (2004) IkappaB kinases: key regulators of the NF-kappaB pathway. Trends Biochem Sci 29:72–79

    PubMed  CAS  Google Scholar 

  • Ye ZC, Sontheimer H (1999) Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 59:4383–4391

    PubMed  CAS  Google Scholar 

  • Ye ZC, Rothstein JD, Sontheimer H (1999) Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. J Neurosci 19:10767–10777

    PubMed  CAS  Google Scholar 

  • Yeh TH, Hwang HM, Chen JJ, Wu T, Li AH, Wang HL (2005) Glutamate transporter function of rat hippocampal astrocytes is impaired following the global ischemia. Neurobiol Dis 18:476–483

    PubMed  CAS  Google Scholar 

  • Yernool D, Boudker O, Jin Y, Gouaux E (2004) Structure of a glutamate transporter homologue from Pyrococcus horikoshii. Nature 431:811–818

    PubMed  CAS  Google Scholar 

  • Zelenaia O, Schlag BD, Gochenauer GE, Ganel R, Song W, Beesley JS, Grinspan JB, Rothstein JD, Robinson MB (2000) Epidermal growth factor receptor agonists increase expression of glutamate transporter GLT-1 in astrocytes through pathways dependent on phosphatidylinositol 3-kinase and transcription factor NF-kappaB. Mol Pharmacol 57:667–678

    PubMed  CAS  Google Scholar 

  • Zelenaia OA, Robinson MB (2000) Degradation of glial glutamate transporter mRNAs is selectively blocked by inhibition of cellular transcription. J Neurochem 75:2252–2258

    PubMed  CAS  Google Scholar 

  • Zerangue N, Arriza JL, Amara SG, Kavanaugh MP (1995) Differential modulation of human glutamate transporter subtypes by arachidonic acid. J Biol Chem 270:6433–6435

    PubMed  CAS  Google Scholar 

  • Zhou J, Sutherland ML (2004) Glutamate transporter cluster formation in astrocytic processes regulates glutamate uptake activity. J Neurosci 24:6301–6306

    PubMed  CAS  Google Scholar 

  • Zink M, Schmitt A, Henn FA, Gass P (2004) Differential expression of glutamate transporters EAAT1 and EAAT2 in mice deficient for PACAP-type I receptor. J Neural Transm 111:1537–1542

    PubMed  CAS  Google Scholar 

  • Zschocke J, Bayatti N, Behl C (2005) Caveolin and GLT-1 gene expression is reciprocally regulated in primary astrocytes: association of GLT-1 with non-caveolar lipid rafts. Glia 49:275–287

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University, 600 N Wolfe Street, Meyer 6-109, Baltimore, MD, 21287, USA

    R. Sattler & J. D. Rothstein

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  1. R. Sattler
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  2. J. D. Rothstein
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  1. Institute of Pharmacology Center for Biomolecular Medicine and Pharmacology, Medical University Vienna, Waehringer Str. 13a, A-1090, Wien, Austria

    Harald H. Sitte  & Michael Freissmuth  & 

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Sattler, R., Rothstein, J.D. (2006). Regulation and Dysregulation of Glutamate Transporters. In: Sitte, H.H., Freissmuth, M. (eds) Neurotransmitter Transporters. Handbook of Experimental Pharmacology, vol 175. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-29784-7_14

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