Abstract
As the primary excitatory neurotransmitter in the mammalian CNS, l-glutamateparticipates not only in standard fast synaptic communication, but also contributes to higher order signalprocessing, as well as neuropathology. Given this variety of functional roles, interest has been growingas to how the extracellular concentrations of l-glutamate surroundingneurons are regulated by cellular transporter proteins. This review focuses on two prominent systems, eachof which appears capable of influencing both the signaling and pathological actions of l-glutamatewithin the CNS: the sodium-dependent excitatory amino acid transporters (EAATs) and the glutamate/cystineexchanger, system x c −(Sx c −). Whilethe family of EAAT subtypes limit access to glutamate receptors by rapidly and efficiently sequesteringl-glutamate in neurons and glia, Sxc −provides a route for the export of glutamate from cells into the extracellular environment. The primaryintent of this work is to provide an overview of the inhibitors and substrates that have been developedto delineate the pharmacological specificity of these transport systems, as well as be exploited as probeswith which to selectively investigate function. Particular attention is paid to the development of smallmolecule templates that mimic the structural properties of the endogenous substrates, l-glutamate,l-aspartate and l-cystine andhow strategic control of functional group position and/or the introduction of lipophilic R-groups can impactmultiple aspects of the transport process, including: subtype selectivity, inhibitory potency, and substrateactivity.
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Balazs R, Bridges RJ, Cotman CW (2006) Excitatory amino acid transmission in health and disease. Oxford University Press, New York
Natale N, Magnusson K, Nelson J (2006) Curr Top Med Chem 6:823
Foster A, Kemp J (2006) Curr Opin Pharmacol 6:7
Waxman E, Lynch D (2005) Neuroscientist 11:37
Hynd MR, Scott HL, Dodd PR (2004) Neurochem Int 45:583
Olney JW (2003) Curr Opin Pharmacol 3:101
Rao SD, Weiss JH (2004) Trends Neurosci 27:17
Coyle J, Tsai G (2004) Psychopharmacology 174:32
Niswender CM, Jones CK, Conn PJ (2005) Curr Top Med Chem 5:847
Recasens M, Guiramand J, Aimar R, Abdulkarim A, Barbanel G (2007) Curr Drug Targets 8:651
Meldrum BS, Chapman AG (1999) Adv Neurol 79:965
Varney M, Gereau R (2002) Curr Drug Targets CNS Neurol Disord 1:283
Danbolt NC (2001) Prog Neurobiol 65:1
Borre L, Kavanaugh MP, Kanner BI (2002) J Biol Chem 277:13501
Gonzalez MI, Robinson MB (2004) Curr Opin Pharmacol 4:30
Diamond JS (2005) J Neurosci 25:2906
Kanner BI (2006) J Membr Biol 21:89
Dunlop J (2006) Curr Opin Pharmacol 6:103
Wadiche JI, Tzingounis AV, Jahr CE (2006) Proc Natl Acad Sci USA 103:1083
Farinelli SE, Nicklas WJ (1992) J Neurochem 58:1905
Choi DW (1994) Prog Brain Res 100:47
Rothman SM, Olney JW (1995) Trends Neurosci 18:57
Mattson MP (2003) Neuromolecular Med 3:65
Hara MR, Snyder SH (2007) Annu Rev Pharmacol Toxicol 47:117
Maragakis NJ, Rothstein JD (2004) Neurobiol Dis 15:461
Aarts MM, Tyminski M (2003) Biochem Pharmacol 66:877
Boillee S, Vande Velde C, Cleveland DW (2006) Neuron 52:39
Logan WJ, Snyder SH (1972) Brain Res 42:413
Storck T, Schulte S, Hofmann K, Stoffel W (1992) Proc Natl Acad Sci USA 89:10955
Pines G, Danbolt NC, Bjoras M, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J, Kanner BI (1992) Nature 360:464
Kanai Y, Hediger MA (1992) Nature 360:467
Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG (1994) J Neurosci 14:5559
Arriza JL, Eliasof S, Kavanaugh MP, Amara SG (1997) Proc Natl Acad Sci USA 94:4155
Fairman W, Vandenberg RJ, Arriza JL, Kavanaugh MP, Amara SG (1995) Nature 375:599
Hediger MA, Romero MF, Peng JB, Rolfs A, Takanaga H, Bruford EA (2004) Pflugers Arch Eur J Physiol 447:465
Palacin M, Estevez R, Bertran J, Zorzano A (1998) Physiol Rev 78:969
Gegelashvili G, Schousboe A (1998) Brain Res Bull 45:233
Wadiche JI, Arriza JL, Amara SG, Kavanaugh MP (1995) Neuron 14:1019
Boudker O, Ryan RM, Yernool D, Shimamoto K, Gouaux E (2007) Nature 445:387
Zerangue N, Kavanaugh MP (1996) Nature 383:634
Wadiche JI, Amara SG, Kavanaugh MP (1995) Neuron 15:721
Otis TS, Kavanaugh M (2000) J Neurosci 20:2749
Yernool D, Boudker O, Jin Y, Gouaux E (2004) Nature 431:811
Haugeto O, Ullensvang K, Levy LM, Chaudhry FA, Honore T, Nielsen M, Lehre KP, Danbolt NC (1996) J Biol Chem 271:27715
Eskandari S, Kreman M, Kavanaugh MP, Wright EM, Zampighi GA (2000) Proc Natl Acad Sci USA 97:8641
Beliveau R, Demeule M, Jette M, Potier M (1990) Biochem J 268:195
Arriza JL, Kavanaugh MP, Fairman WA, Wu Y, Murdoch GH, North RA, Amara SG (1993) J Biol Chem 268:15329
Koch HP, Kavanaugh MP, Esslinger CS, Zerangue N, Humphrey JM, Amara SG, Chamberlin AR, Bridges RJ (1999) Mol Pharmacol 56:1095
Balcar VS, Johnston GAR (1972) J Neurobiol 3:295
Roberts PJ, Watkins JC (1975) Brain Res 85:120
Vandenberg RJ, Mitrovic AD, Chebib M, Balcar VJ, Johnston GAR (1997) Mol Pharmacol 51:809
Lebrun B, Sakaitani M, Shimamoto K, Yasuda-Kamatani Y, Nakajima T (1997) J Biol Chem 272:20336
Chamberlin AR, Koch HP, Bridges RJ (1998) In: Amara SG (ed) Neurotransmitter Transporters (Meth Enzymol), vol 296. Academic Press, San Diego, p 175
Esslinger CS, Agarwal S, Gerdes JM, Wilson PA, Davies ES, Awes AN, O'Brien E, Mavencamp T, Koch HP, Poulsen DJ, Chamberlin AR, Kavanaugh MP, Bridges RJ (2005) Neuropharmacology 49:850
Esslinger CS, Titus J, Koch HP, Bridges RJ, Chamberlin AR (2002) Bioorg Med Chem 10:3509
Dunlop J, McIlvain B, Carrick T, Jow B, Lu Q, Kowal DM, Lin S, Greenfield A, Grosanu C, Fan K, Petroski R, Williams J, Foster A, Butera J (2005) Mol Pharmacol 68:974
Shigeri Y, Shimamoto K, Yasuda-Kamatani Y, Seal RP, Yumoto N, Nakajima T, Amara SG (2001) J Neurochem 79:297
Shimamoto K, LeBrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T (1998) Mol Pharmacol 53:195
Shimamoto K, Sakai R, Takaoka K, Yumoto N, Nakajima T, Amara SG, Shigeri Y (2004) Mol Pharmacol 65:1008
Shimamoto K, Otsubo Y, Shigeri Y, Yasuda-Kamatani Y, Satoh M, Kaneko T, Nakagawa T (2007) Mol Pharmacol 71:294
Rudnick G (1997) In: Mea R (ed) Neurotransmitter transporters, structure, function and regulation. Humana Press, New Jersey, p 73
Tatsumi M, K. G, Blakely R, Richelson E (1997) Eur J Pharmacol 340:249
Alaux S, Kusk M, Sagot E, Bolte J, Jensen A, Brauner-Osborne H, Gefflaut T, Bunch L (2005) J Med Chem 48:7980
Greenfield A, Grosanu C, Dunlop J, McIlvain B, Carrick T, Jow B, Lu Q, Kowal DM, Williams J, Butera J (2005) Bioorg Med Chem Lett 15:4985
Dunlop J, McIlvain HB, Carrick T, Jow B, Lu Q, Kowal DM, Lin S, Greenfield A, Grosanu C, Fan K, Petroski R, Williams J, Foster A, Butera J (2005) Mol Pharmacol 68:974
Ishida M, Ohfune Y, Shimada Y, Shimamoto K, Shinozaki H (1991) Brain Res 550:152
Nakagawa Y, Saitoh K, Ishihara T, Ishida M, Shinozaki H (1990) Eur J Pharmacol 184:205
Nakamura Y, Kataoka K, Ishida M, Shinozaki H (1993) Neuropharmacology 32:833
Yamashita H, Kawakami H, Zhang Y, Hagiwara T, Tanaka K, Nakamura S (1995) Eur J Pharmacol 289:387
Dowd LA, Coyle AJ, Rothstein JD, Pritchett DB, Robinson MB (1996) Mol Pharmacol 49:465
Faure S, Jensen A, Maurat V, Gu X, Sagot E, Aitken D, Bolte J, Gefflaut T, Bunch L (2006) J Med Chem 49:6532
Jensen A, Brauner-Osborne H (2004) Biochem Pharmacol 67:2115
Johnston GAR, Kennedy SME, Twitchin B (1979) J Neurochem 32:121
Bridges RJ, Stanley MS, Anderson MW, Cotman CW, Chamberlin AR (1991) J Med Chem 34:717
Willis CL, Humphrey JM, Koch HP, Hart JA, Blakely T, Ralston L, Baker CA, Shim S, Kadri M, Chamberlin AR, Bridges RJ (1996) Neuropharmacology 35:531
Stensbol TB, Uhlmann P, Morel S, Eriksen BL, Felding J, Kromann H, Hermit MB, Greenwood JR, Brauner-Osborne H, Madsen U, Junager F, Krogsgaard-Larsen P, Begtrup M, Vedso P (2002) J Med Chem 45:19
Brauner-Osborne H, Hermit MB, Nielsen B, Krogsgaard-Larsen P, Johansen TN (2000) Eur J Pharmacol 406:41
Campiani G, De Angelis M, Armaroli S, Fattorusso C, Catalanotti B, Ramunno A, Nacci V, Novellino E, Grewer C, Ionescu D, Rauen T, Griffiths R, Sinclair C, Fumagalli E, Mennini T (2001) J Med Chem 44:2507
Campiani G, Fattorusso C, De Angelis M, Catalanotti B, Butini S, Fattorusso S, Fiorini I, Nacci V, Novellino E (2003) Curr Pharm Des 9:599
Dunlop J, Eliasof S, Stack G, McIlvain HB, Greenfield A, Kowal DM, Petroski R, Carrick T (2003) Br J Pharmacol 140:839–846
Dunlop J, Butera J (2006) Curr Top Med Chem 6:1897
Barbour B, Keller BU, Liana I, Marty A (1994) Neuron 12:1331
Isaacson JS, Nicoll RA (1993) J Neurophysiol 70:2187
Sarantis M, Ballerini L, Miller B, Silver RA, Edwards M, Attwell D (1993) Neuron 11:541
Wadiche JI, Jahr CE (2001) Neuron 32:301
Matsui K, Hosoi N, Tachibana M (1999) J Neurosci 19:6755
Kinney GA, Overstreet LS, Slater NT (1997) J Neurophysiol 78:1320
Overstreet LS, Kinney GA, Liu YB, Billups D, Slater NT (1999) J Neurosci 19:9663
Turecek R, Trussell LO (2000) J Neurosci 20:2054
Dzubay JA, Otis TS (2002) Neuron 36:1159
Higgs MH, Lukasiewicz PD (1999) J Neurosci 19:3691
Brasnjo G, Otis TS (2001) Neuron 31:607
Scanziani M, Salin PA, Vogt KE, Malenka RC, Nicoll R (1997) Nature 385:630
Semyanov A, Kullmann DM (2000) Neuron 25:663
Asztely F, Erdemli G, Kullmann DM (1997) Neuron 18:281
Carter AG, Regehr WG (2000) J Neurosci 20:4423
Isaacson JS (1999) Neuron 23:377
Diamond JS, Jahr CE (2000) J Neurophysiol 83:2835
Cho Y, Bannai S (1990) J Neurochem 55:2091
Baker DA, Shen H, Kalivas PW (2002) Amino Acids 23:161
Baker DA, Xi ZX, Hui S, Swanson CJ, Kalivas PW (2002) J Neurosci 22:9134
Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW (2003) Nat Neurosci 6:743
McBean GJ, Roberts PJ (1985) J Neurochem 44:247
Robinson MB, Djali S, Buchhalter JR (1993) J Neurochem 61:586
Amin N, Pearce B (1997) Neurochem Int 30:271
Velasco I, Tapia R, Massieu L (1996) J Neurosci Res 44:551
Rothstein JD, Jin L, Dykes-Hoberg M, Kuncl RW (1993) Proc Natl Acad Sci USA 90:6591
Montiel T, Camacho A, Estrada-Sanchez A, Massieu L (2005) Neuroscience 133:667
Anderson CM, Bridges RJ, Chamberlin AR, Shimamoto K, Yasuda-Kamatani Y, Swanson RA (2001) J Neurochem 79:1207
Koch HP, Chamberlin AR, Bridges RJ (1999) Mol Pharmacol 55:1044
Bonde C, Sarup A, Schousboe A, Gegelashvilli G, Zimmer J, Noraberg J (2003) Neurochem Int 43:371
Marcaggi P, Hirji N, Attwell D (2005) Neuropharmacology 49:843
Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Neuron 16:675
Rao V, Dogan A, K. B, Todd K, Dempsey RJ (2001) Eur J Neurosci 13:119
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) Science 276:1699
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) Eur J Neurosci 10:976
Peghini P, Janzen J, Stoffel W (1997) EMBO J 16:3822
Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Y. C, Swanson RA (2006) Nat Neurosci 9:119
Matsugami T, Tanemura K, Mieda M, Nakatomi R, Yamada K, Kono T, Ogawa M, Obata K, Watanabe M, Hashikawa T, Tanaka K (2006) Proc Natl Acad Sci USA 103:12161
Zerangue N, Arriza JL, Amara SG, Kavanaugh MP (1995) J Biol Chem 270:6433
Rothstein J, Patel S, Regan M, Haenggeli C, Huang Y, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung D, Toan S, Bruijn L, Su Z, Gupta P, Fisher P (2005) Nature 433:73
Kranich O, Dringen R, Sandberg M, Hamprecht B (1998) Glia 22:11
Shih A, Erb H, Sun X, Toda S, Kalivas P, Murphy T (2006) J Neurosci 41:10514
Hosoya K, Tomi M, Ohtsuki S, Takanaga H, Saeki S, Kanai Y, Endou H, Naito M, Tsuruo T, Terasaki T (2002) J Pharmacol Exp Ther 302:225
Augustin H, grosjean Y, Chen K, Sheng Q, Featherstone D (2007) J Neurosci 27:111
Palacin M, Nunes V, Jimenez-Vidal M, Font-Llitjos M, Gasol E, Pineda M, Feliubadalo L, Chillaron J, Zorzano A (2005) Physiology 20:112
Sato H, Tamba M, Ishii T, Bannai S (1999) J Biol Chem 274:11455
Gasol E, Jimenez-Vidal M, Chillaron J, Zorzano A, Palacin M (2004) J Biol Chem 279:31228
Jimenez-Vidal M, Gasol E, Zorzano A, Nunes V, Palacin M, Chillaron J (2004) J Biol Chem 279:11214
Kaleeba JA, Berger EA (2006) Science 311:1921
Nakamura E, Sato M, Yang H, Miyagawa F, Harasaki M, Tomita K, Matsuoka S, Noma A, Iwai K, Minato N (1999) J Biol Chem 274:3009
Palacin M, Kanai Y (2004) Eur J Physiol 447:490
Allen JW, Shanker G, Aschner M (2001) Brain Res 894:131
Gochenauer GE, Robinson MB (2001) J Neurochem 78:276
Piani D, Fontana A (1994) J Immunol 3578
Kato S, Ishita S, Sugawara K, Mawatari K (1993) Neuroscience 57:473
Murphy TH, Schnaar RL, Coyle JT (1990) FASEB J 4:1624
Ye Z, Rothstein JD, Sontheimer H (1999) J Neurosci 19:10767
Sasaki H, Sato H, Kuriyama M, K., Sato K, Maebara K, Wang H, Tamba M, Itoh K, Yamamoto A, Bannai S (2002) J Biol Chem 274:44765
Bannai S, Takada A, Kasuga H, Tateishi N (1986) Hepatology 6:1361
Bannai S, Kitamura E (1981) J Biol Chem 256:5770
Bannai S (1986) J Biol Chem 261:2256
Fagg GE, Foster AC, Mena EE, Cotman CW (1982) J Neurosci 2:958
Pin JP, Bockaert J, Recasen M (1984) FEBS Lett 175:31
Bridges RJ, Hearn TJ, Monaghan DT, Cotman CW (1986) Brain Res 375:204
Bridges RJ, Nieto SM, Kadri M, Cotman CW (1987) J Neurochem 48:001
Kessler M, Baudry M, Lynch G (1987) Neurosci Lett 81:221
Anderson KJ, Monaghan DT, Bridges RJ, Tavoularis AL, Cotman CW (1990) Neuroscience 38:311
Murphy TH, Miyamoto M, Sastre A, Schnaar RL, Coyle JT (1989) Neuron 2:1547
Waniewski RA, Martin DL (1984) J Neurosci 4:2237
Warren BA, Patel SA, Nunn PB, Bridges RJ (2004) Toxicol Appl Pharmacol 200:83
Patel SA, Warren BA, Rhoderick JF, Bridges RJ (2004) Neuropharmacology 46:273
Huang Y, Barbacioru C, Sadee W (2005) Cancer Res 65:7446
Ebert B, Madsen U, Johansen TN, Krogsgaard-Larsen P (1991) Adv Exp Med Biol 287:483
Brauner-Osborne H, Krogsgaard-Larsen P (1998) Eur J Pharmacol 5:311
Coquelle T, Christensen JK, Banke TG, Madsen U, Schousboe A, Pickering DS (2000) Neuroreport 21:2643
Wong LA, Mayer ML, Jane DE, Watkins JC (1994) J Neurosci 14:3881
Bedingfield JS, Kemp MC, Jane DE, Tse HW, Roberts PJ, Watkins JC (1995) Br J Pharmacol 116:3323
Chung WJ, Lyons SA, Nelson GM, Hamza H, Gladson CL, Gillespie GY, Sontheimer H (2005) J Neurosci 25:7101
Ye ZC, Sontheimer H (1999) Cancer Res 59:4383
Nicholls DG, Sihra TS, Sanches-Prieto J (1987) J Neurochem 1987:50
Chase LA, Roon RJ, Wellman L, Beitz AJ, Koerner JF (2001) Neuroscience 106:287
Wang XF, Cynader MS (2000) J Neurochem 74:1434
Guebel DV, Torres NV (2004) Biochim Biophys Acta 1674:12
Dringen R, Gutterer JM, Gros C, Hirrlinger J (2001) J Neurosci Res 66:1003
Sun X, Erb H, Murphy TH (2005) Biochem Biophys Res Commun 326:371
Sato H, Nomura S, Maebara K, Sato K, Tamba M, Bannai S (2004) Biochem Biophys Res Commun 325:109
Kim JY, Kanai Y, Chairoungdua A, Cha SH, Matsuo H, Kim DK, Inatomim J, Sawa H, Ida Y, Endou H (2001) Biochim Biophys Acta 1512:335
Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M (2000) J Biol Chem 275:16023
Nagasawa M, Ito S, Kakuda T, Nagai K, Tamai I, Tsuji A, Fujimoto S (2005) Toxicol Lett 155:289
Bender AS, Reichelt W, Norenberg MD (2000) Neurochem Int 37:269
McBean GJ, Flynn J (2001) Biochem Soc Trans 29:717
Zerangue N, Kavanaugh MP (1996) J Physiol 493:419
Chen Y, Swanson RA (2003) J Neurochem 84:1332
Barger SW, Basile AS (2001) J Neurochem 76:846
Takano T, Lin J, G. A, Gao Q, Yang J, Nedergaard M (2001) Nat Med 7:1010
Gout PW, Buckley AR, Simms CR, Bruchovsky N (2001) Leukemia 15:1633
Moran M, McFarland K, Melendez RI, Seamans JK (2005) J Neurosci 25:6389
Melendez RI, Vuthiganon J, Kalivas PW (2005) J Pharmacol Exp Ther 314:139
Warr O, Takahashi M, Attwell D (1999) J Physiol 514.3:783
Cavelier P, Attwell D (2005) J Physiol 564:397
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Bridges, R.J., Patel, S.A. (2008). Pharmacology of Glutamate Transport in the CNS: Substrates and Inhibitors of Excitatory Amino Acid Transporters (EAATs) and the Glutamate/Cystine Exchanger System x c − . In: Napier, S., Bingham, M. (eds) Transporters as Targets for Drugs. Topics in Medicinal Chemistry, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2008_026
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