Glutamate transporters: Confining runaway excitation by shaping synaptic transmission

Nature Reviews Neuroscience

Volumn 8, Issue 12, 2007, Pages 935-947

  Tzingounis, Anastassios V ^a   Wadiche, Jacques I ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b University of Alabama at Birmingham   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 [3 [4 (TRIFLUOROMETHYL)BENZOYLAMINO]BENZYLOXY]ASPARTATE; 4 AMINOBUTYRIC ACID; AMPA RECEPTOR; ASPARTIC ACID DERIVATIVE; CYCLOTHIAZIDE; DIHYDROKAINIC ACID; GLUTAMATE TRANSPORTER; LITHIUM; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG;

CEREBELLUM; GRANULE CELL; HIPPOCAMPUS; MOSSY FIBER; NERVE CELL PLASTICITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN STRUCTURE; PURKINJE CELL; RECEPTOR AFFINITY; RECEPTOR BLOCKING; RETINA; REVIEW; STOICHIOMETRY; SYNAPSE; SYNAPTIC TRANSMISSION; THERMODYNAMICS;

AMINO ACID TRANSPORT SYSTEM X-AG; ANIMALS; GLUTAMIC ACID; HUMANS; NEURONAL PLASTICITY; SYNAPTIC TRANSMISSION;

HARNESS;

EID: 36348975209     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn2274     Document Type: Review

References (145)

1. Allen, N. J., Karadottir, R. & Attwell, D. Reversal or reduction of glutamate and GABA transport in CNS pathology and therapy. Pflugers Arch. 449, 132-142 (2004).
2. Maragakis, N. J. & Rothstein, J. D. Mechanisms of disease: astrocytes in neurodegenerative disease. Nature Clin. Pract. Neurol. 2, 679-689 (2006).
3. Beart, P. M. & O'Shea, R. D. Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br. J. Pharmacol. 150, 5-17 (2007).
4. Tilleux, S. & Hermans, E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J. Neurosci. Res. 85, 2059-2070 (2007).
5. Stern, J. R., Eggleston, L. V., Hems, R. & Krebs, H. A. Accumulation of glutamic acid in isolated brain tissue. Biochem. J. 44, 410-418 (1949).
6. Kanner, B. I. & Sharon, I. Active transport of L-glutamate by membrane vesicles isolated from rat brain. Biochemistry 17, 3949-3953 (1978).
7. Kanner, B. I. & Schuldiner, S. Mechanism of transport and storage of neurotransmitters. CRC Crit. Rev. Biochem. 22, 1-38 (1987).
8. Danbolt, N. C. Glutamate uptake. Prog. Neurobiol. 65, 1-105 (2001).
9. Kanai, Y. & Hediger, M. A. Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360, 467-471 (1992).
10. Pines, G. et al. Cloning and expression of a rat brain L-glutamate transporter. Nature 360, 464-467 (1992).
11. +-dependent glutamate/aspartate transporter from rat brain. Proc. Natl Acad. Sci. USA 89, 10955-10959 (1992).
12. Arriza, J. L. et al. Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J. Neurosci. 14, 5559-5569 (1994).
13. Fairman, W. A., Vandenberg, R. J., Arriza, J. L., Kavanaugh, M. P. & Amara, S. G. An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375, 599-603 (1995).
14. Arriza, J. L., Eliasof, S., Kavanaugh, M. P. & Amara, S. G. Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc. Natl Acad. Sci. USA 94, 4155-4160 (1997).
15. Kavanaugh, M. P. Neurotransmitter transport: models in flux. Proc. Natl Acad. Sci. USA 95, 12737-12738 (1998).
16. Barbour, B., Brew, H. & Attwell, D. Electrogenic glutamate uptake in glial cells is activated by intracellular potassium. Nature 335, 433-435 (1988).
17. Klockner, U., Storck, T., Conradt, M. & Stoffel, W. Electrogenic L-glutamate uptake in Xenopus laevis oocytes expressing a cloned rat brain L-glutamate/L-aspartate transporter (GLAST-1). J. Biol. Chem. 268, 14594-14596 (1993).
18. Stallcup, W. B., Bulloch, K. & Baetge, E. E. Coupled transport of glutamate and sodium in a cerebellar nerve cell line. J. Neurochem. 32, 57-65 (1979).
19. Kanner, B. I. & Bendahan, A. Binding order of substrates to the sodium and potassium ion coupled L-glutamic acid transporter from rat brain. Biochemistry 21, 6327-6330 (1982).
20. Erecinska, M., Wantorsky, D. & Wilson, D. F. Aspartate transport in synaptosomes from rat brain. J. Biol. Chem. 258, 9069-9077 (1983).
21. Bouvier, M., Szatkowski, M., Amato, A. & Attwell, D. The glial cell glutamate uptake carrier countertransports pH-changing anions. Nature 360, 471-474 (1992).
22. Kanai, Y. et al. Electrogenic properties of the epithelial and neuronal high affinity glutamate transporter. J. Biol. Chem. 270, 16561-16568 (1995).
23. Wadiche, J. I., Arriza, J. L., Amara, S. G. & Kavanaugh, M. P. Kinetics of a human glutamate transporter. Neuron 14, 1019-1027 (1995).
24. Zerangue, N. & Kavanaugh, M. P. Interaction of L-cysteine with a human excitatory amino acid transporter. J. Physiol. 493, 419-423 (1996).
25. Zerangue, N. & Kavanaugh, M. P. Flux coupling in a neuronal glutamate transporter. Nature 383, 634-637 (1996). The definitive paper that determined the number of ions that are coupled to glutamate uptake, by measuring the reversal potential of glutamate transporters under different extracellular ionic conditions.
26. +-dependent glutamate uptake. J. Neurosci. 18, 9620-9628 (1998).
27. Owe, S. G., Marcaggi, P. & Attwell, D. The ionic stoichiometry of the GLAST glutamate transporter in salamander retinal glia. J. Physiol. 577, 591-599 (2006).
28. Herman, M. A. & Jahr, C. E. Extracellular glutamate concentration in hippocampal slice. J. Neurosci. 27, 9736-9741 (2007). Using NMDA receptors as a 'sniffer', this article provided a quantitative measurement of the glutamate concentration in the extracellular space.
29. Cavelier, P. & Attwell, D. Tonic release of glutamate by a DIDS-sensitive mechanism in rat hippocampal slices. J. Physiol. 564, 397-410 (2005).
30. Sah, P., Hestrin, S. & Nicoll, R. A. Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. Science 246, 815-818 (1989).
31. Lerma, J., Herranz, A. S., 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).
32. McGann, J. P. et al. Odorant representations are modulated by intra- but not interglomerular presynaptic inhibition of olfactory sensory neurons. Neuron 48, 1039-1053 (2005).
33. - and other anions readily permeate EAATs, and that this uncoupled conductance does not influence glutamate uptake.
34. Vandenberg, R. J., Mitrovic, A. D. & Johnston, G. A. Serine-O-sulphate transport by the human glutamate transporter, EAAT2. Br. J. Pharmacol. 123, 1593-1600 (1998).
35. Ryan, R. M. & Mindell, J. A. The uncoupled chloride conductance of a bacterial glutamate transporter homolog. Nature Struct. Mol. Biol. 14, 365-371 (2007). Using a fluorescence assay to detect anion flux, this study provided the first evidence that glutamate transporters allow the flow of anions in the absence of any additional subunits.
36. Lehre, K. P. & Danbolt, N. C. 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). This rigorous study used quantitative immunoblotting to determine the number of glial and neuronal transporters in different regions of the brain. The authors concluded that the number of glial transporters is sufficiently high to clear the number of glutamate molecules released per vesicle.
37. Dehnes, Y. et al. 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).
38. Haugeto, O. et al. Brain glutamate transporter proteins form homomultimers. J. Biol. Chem. 271, 27715-27722 (1996).
39. Eskandari, S., Kreman, M., Kavanaugh, M. P., Wright, E. M. & Zampighi, G. A. Pentameric assembly of a neuronal glutamate transporter. Proc. Natl Acad. Sci. USA 97, 8641-8646 (2000).
40. Yernool, D., Boudker, O., Jin, Y. & Gouaux, E. Structure of a glutamate transporter homologue from Pyrococcus horikoshii. Nature 431, 811-818 (2004). This article provided the first crystal structure of a glutamate transporter family member. It offered direct evidence that transporters are homotrimers and that the glutamate-binding site is sandwiched between two hairpin loops, presumably the transport gates. The article also suggested that an alternating-access mechanism mediates glutamate transport.
41. Koch, H. P. & Larsson, H. P. Small-scale molecular motions accomplish glutamate uptake in human glutamate transporters. J. Neurosci. 25, 1730-1736 (2005).
42. Grewer, C. et al. Individual subunits of the glutamate transporter EAAC1 homotrimer function independently of each other. Biochemistry 44, 11913-11923 (2005).
43. Koch, H. P., Brown, R. L. & Larsson, H. P. The glutamate-activated anion conductance in excitatory amino acid transporters is gated independently by the individual subunits. J. Neurosci. 27, 2943-2947 (2007).
44. Boudker, O., Ryan, R. M., 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).
45. Otis, T. S. & Jahr, C. E. Anion currents and predicted glutamate flux through a neuronal glutamate transporter. J. Neurosci. 18, 7099-7110 (1998).
46. Bergles, D. E. & Jahr, C. E. Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus. J. Neurosci. 18, 7709-7716 (1998).
47. Otis, T. S. & Kavanaugh, M. P. Isolation of current components and partial reaction cycles in the glial glutamate transporter EAAT2. J. Neurosci. 20, 2749-2757 (2000).
48. Auger, C. & Attwell, D. Fast removal of synaptic glutamate by postsynaptic transporters. Neuron 28, 547-558 (2000).
49. Koch, H. P., Hubbard, J. M. & Larsson, H. P. Voltage-independent sodium-binding events reported by the 4B-4C loop in the human glutamate transporter EAAT3. J. Biol. Chem. 282, 24547-24553 (2007).
50. Tolner, B., Poolman, B. & Konings, W. N. Adaptation of microorganisms and their transport systems to high temperatures. Comp. Biochem. Physiol. A Physiol. 118, 423-428 (1997).
51. Malenka, R. C. & Nicoll, R. A. Long-term potentiation-a decade of progress? Science 285, 1870-1874 (1999).
52. Tanaka, K. et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276, 1699-1702 (1997).
53. Lehre, K. P., Levy, L. M., Ottersen, O. P., Storm-Mathisen, J. & Danbolt, N. C. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J. Neurosci. 15, 1835-1853 (1995).
54. Chaudhry, F. A. et al. Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron 15, 711-720 (1995).
55. Rothstein, J. D. et al. Localization of neuronal and glial glutamate transporters. Neuron 13, 713-725 (1994).
56. Chen, W. et al. The glutamate transporter GLT1a is expressed in excitatory axon terminals of mature hippocampal neurons. J. Neurosci. 24, 1136-1148 (2004).
57. Furuta, A., Rothstein, J. D. & Martin, L. J. Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J. Neurosci. 17, 8363-8375 (1997).
58. Hestrin, S., Sah, P. & Nicoll, R. A. Mechanisms generating the time course of dual component excitatory synaptic currents recorded in hippocampal slices. Neuron 5, 247-253 (1990).
59. Sarantis, M. et al. Glutamate uptake from the synaptic cleft does not shape the decay of the non-NMDA component of the synaptic current. Neuron 11, 541-549 (1993).
60. Isaacson, J. S. & Nicoll, R. A. The uptake inhibitor L-trans-PDC enhances responses to glutamate but fails to alter the kinetics of excitatory synaptic currents in the hippocampus. J. Neurophysiol. 70, 2187-2191 (1993).
61. Diamond, J. S. Neuronal glutamate transporters limit activation of NMDA receptors by neurotransmitter spillover on CA1 pyramidal cells. J. Neurosci. 21, 8328-8338 (2001).
62. Arnth-Jensen, N., Jabaudon, D. & Scanziani, M. Cooperation between independent hippocampal synapses is controlled by glutamate uptake. Nature Neurosci. 5, 325-331 (2002).
63. Tsukada, S., Iino, M., Takayasu, Y., Shimamoto, K. & Ozawa, S. Effects of a novel glutamate transporter blocker, (2S, 3S)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy] aspartate (TFB-TBOA), on activities of hippocampal neurons. Neuropharmacology 48, 479-491 (2005).
64. Partin, K. M., Patneau, D. K. & Mayer, M. L. Cyclothiazide differentially modulates desensitization of α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor splice variants. Mol. Pharmacol. 46, 129-138 (1994).
65. Fucile, S., Miledi, R. & Eusebi, F. Effects of cyclothiazide on GluR1/AMPA receptors. Proc. Natl Acad. Sci. USA 103, 2943-2947 (2006).
66. Diamond, J. S. & Jahr, C. E. Asynchronous release of synaptic vesicles determines the time course of the AMPA receptor-mediated EPSC. Neuron 15, 1097-1107 (1995).
67. Mennerick, S. & Zorumski, C. F. Glial contributions to excitatory neurotransmission in cultured hippocampal cells. Nature 368, 59-62 (1994).
68. Tong, G. & Jahr, C. E. Block of glutamate transporters potentiates postsynaptic excitation. Neuron 13, 1195-1203 (1994). Using low-affinity antagonists to measure the lifetime of glutamate in the synapse, this paper suggested that glutamate transporters clear glutamate first through rapid binding/buffering and then through slow transport.
69. Diamond, J. S. & Jahr, C. E. Transporters buffer synaptically released glutamate on a submillisecond time scale. J. Neurosci. 17, 4672-4687 (1997).
70. Ventura, R. & Harris, K. M. Three-dimensional relationships between hippocampal synapses and astrocytes. J. Neurosci. 19, 6897-6906 (1999).
71. Lozovaya, N. A., Kopanitsa, M. V., Boychuk, Y. A. & Krishtal, O. A. Enhancement of glutamate release uncovers spillover-mediated transmission by N-methyl-D-aspartate receptors in the rat hippocampus. Neuroscience 91, 1321-1330 (1999).
72. Sepkuty, J. P. et al. A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy. J. Neurosci. 22, 6372-6379 (2002).
73. Mathews, G. C. & Diamond, J. S. Neuronal glutamate uptake contributes to GABA synthesis and inhibitory synaptic strength. J. Neurosci. 23, 2040-2048 (2003).
74. Jakab, R. L. & Hamori, J. Quantitative morphology and synaptology of cerebellar glomeruli in the rat. Anat. Embryol. 179, 81-88 (1988).
75. Otis, T. S., Kavanaugh, M. P. & Jahr, C. E. Postsynaptic glutamate transport at the climbing fiber-Purkinje cell synapse. Science 277, 1515-1518 (1997).
76. Wadiche, J. I. & Jahr, C. E. Patterned expression of Purkinje cell glutamate transporters controls synaptic plasticity. Nature Neurosci. 8, 1329-1334 (2005).
77. Huang, Y. H., Dykes-Hoberg, M., Tanaka, K., Rothstein, J. D. & Bergles, D. E. Climbing fiber activation of EAAT4 transporters and kainate receptors in cerebellar Purkinje cells. J. Neurosci. 24, 103-111 (2004).
78. Gincel, D. et al. Analysis of cerebellar Purkinje cells using EAAT4 glutamate transporter promoter reporter in mice generated via bacterial artificial chromosome-mediated transgenesis. Exp. Neurol. 203, 205-212 (2007).
79. Overstreet, L. S., Kinney, G. A., Liu, Y. B., Billups, D. & Slater, N. T. Glutamate transporters contribute to the time course of synaptic transmission in cerebellar granule cells. J. Neurosci. 19, 9663-9673 (1999). This paper provided an early demonstration of how glutamate transporters limit the extent of glutamate spillover during repetitive synaptic stimulation.
80. DiGregorio, D. A., Nusser, Z. & Silver, R. A. Spillover of glutamate onto synaptic AMPA receptors enhances fast transmission at a cerebellar synapse. Neuron 35, 521-533 (2002).
81. Kinney, G. A., Overstreet, L. S. & Slater, N. T. Prolonged physiological entrapment of glutamate in the synaptic cleft of cerebellar unipolar brush cells. J. Neurophysiol. 78, 1320-1333 (1997).
82. Palay, S. L. & Chan-Palay, V. Cerebellar cortex: cytology and organization (Springer, New York, 1974).
83. Spacek, J. Three-dimensional analysis of dendritic spines. III. Glial sheath. Anat. Embryol. 171, 245-252 (1985).
84. Xu-Friedman, M. A., Harris, K. M. & Regehr, W. G. Three-dimensional comparison of ultrastructural characteristics at depressing and facilitating synapses onto cerebellar Purkinje cells. J. Neurosci. 21, 6666-6672 (2001).
85. Barbour, B., Keller, B. U., Llano, I. & Marty, A. Prolonged presence of glutamate during excitatory synaptic transmission to cerebellar Purkinje cells. Neuron 12, 1331-1343 (1994).
86. Marcaggi, P. & Attwell, D. Endocannabinoid signaling depends on the spatial pattern of synapse activation. Nature Neurosci. 8, 776-781 (2005).
87. Takahashi, M., Kovalchuk, Y. & Attwell, D. Pre- and postsynaptic determinants of EPSC waveform at cerebellar climbing fiber and parallel fiber to Purkinje cell synapses. J. Neurosci. 15, 5693-5702 (1995).
88. Wadiche, J. I. & Jahr, C. E. Multivesicular release at climbing fiber-Purkinje cell synapses. Neuron 32, 301-313 (2001).
89. Foster, K. A., Kreitzer, A. C. & Regehr, W. G. Interaction of postsynaptic receptor saturation with presynaptic mechanisms produces a reliable synapse. Neuron 36, 1115-1126 (2002).
90. Hansel, C., Linden, D. J. & D'Angelo, E. Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum. Nature Neurosci. 4, 467-475 (2001).
91. Baude, A. et al. The metabotropic glutamate receptor (mGluR1α) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction. Neuron 11, 771-787 (1993).
92. Brasnjo, G. & Otis, T. S. Neuronal glutamate transporters control activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression. Neuron 31, 607-616 (2001). This paper provided the first demonstration that neuronal glutamate transporters are uniquely positioned to regulate glutamate concentration after synaptic vesicle release.
93. Ozol, K., Hayden, J. M., Oberdick, J. & Hawkes, R. Transverse zones in the vermis of the mouse cerebellum. J. Comp. Neurol. 412, 95-111 (1999).
94. Kim, S. J. et al. Activation of the TRPC1 cation channel by metabotropic glutamate receptor mGluR1. Nature 426, 285-291 (2003).
95. Marcaggi, P., Billups, D. & Attwell, D. The role of glial glutamate transporters in maintaining the independent operation of juvenile mouse cerebellar parallel fibre synapses. J. Physiol. 552, 89-107 (2003).
96. Takayasu, Y., Iino, M., Shimamoto, K., Tanaka, K. & Ozawa, S. Glial glutamate transporters maintain one-to-one relationship at the climbing fiber-Purkinje cell synapse by preventing glutamate spillover. J. Neurosci. 26, 6563-6572 (2006).
97. Szapiro, G. & Barbour, B. Multiple climbing fibers signal to molecular layer interneurons exclusively via glutamate spillover. Nature Neurosci. 10, 735-742 (2007).
98. Pow, D. V., Barnett, N. L. & Penfold, P. Are neuronal transporters relevant in retinal glutamate homeostasis? Neurochem. Int. 37, 191-198 (2000).
99. von Gersdorff, H., Vardi, E., Matthews, G. & Sterling, P. Evidence that vesicles on the synaptic ribbon of retinal bipolar neurons can be rapidly released. Neuron 16, 1221-1227 (1996).
100. Hasegawa, J., Obara, T., Tanaka, K. & Tachibana, M. High-density presynaptic transporters are required for glutamate removal from the first visual synapse. Neuron 50, 63-74 (2006).
101. Matsui, K., Hosoi, N. & Tachibana, M. Active role of glutamate uptake in the synaptic transmission from retinal nonspiking neurons. J. Neurosci. 19, 6755-6766 (1999).
102. Burris, C., Klug, K., Ngo, I. T., Sterling, P. & Schein, S. How Muller glial cells in macaque fovea coat and isolate the synaptic terminals of cone photoreceptors. J. Comp. Neurol. 453, 100-111 (2002).
103. DeVries, S. H., Li, W. & Saszik, S. Parallel processing in two transmitter microenvironments at the cone photoreceptor synapse. Neuron 50, 735-748 (2006).
104. Wersinger, E. et al. The glutamate transporter EAAT5 works as a presynaptic receptor in mouse rod bipolar cells. J. Physiol. 577, 221-234 (2006).
105. Veruki, M. L., Morkve, S. H. & Hartveit, E. Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling. Nature Neurosci. 9, 1388-1396 (2006). This elegant study in retinal slices used a combination of electrophysiological techniques to demonstrate that glutamate spills over to neighbouring bipolar cells, leading to the inhibition of transmitter release through the activation of presynaptic glutamate transporters.
106. Wadiche, J. I. & von Gersdorff, H. Long-distance signaling via presynaptic glutamate transporters. Nature Neurosci. 9, 1352-1353 (2006).
107. Sarantis, M., Everett, K. & Attwell, D. A presynaptic action of glutamate at the cone output synapse. Nature 332, 451-453 (1988).
108. Picaud, S. A., Larsson, H. P., Grant, G. B., Lecar, H. & Werblin, F. S. Glutamate-gated chloride channel with glutamate-transporter-like properties in cone photoreceptors of the tiger salamander. J. Neurophysiol. 74, 1760-1771 (1995).
109. Palmer, M. J., Taschenberger, H., Hull, C., Tremere, L. & von Gersdorff, H. Synaptic activation of presynaptic glutamate transporter currents in nerve terminals. J. Neurosci. 23, 4831-4841 (2003).
110. Grant, G. B. & Dowling, J. E. A glutamate-activated chloride current in cone-driven ON bipolar cells of the white perch retina. J. Neurosci. 15, 3852-3862 (1995).
111. Jackson, M. et al. Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature 410, 89-93 (2001). Using a yeast two-hybrid screen, this study and reference 112 identified the first glutamate-transporter-interacting proteins.
112. Lin, C. I. et al. Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18. Nature 410, 84-88 (2001).
113. Gonzalez, M. I., Bannerman, P. G. & Robinson, M. B. Phorbol myristate acetate-dependent interaction of protein kinase C? and the neuronal glutamate transporter EAAC1. J. Neurosci. 23, 5589-5593 (2003).
114. Gonzalez, M. I., Susarla, B. T. & Robinson, M. B. Evidence that protein kinase C? interacts with and regulates the glial glutamate transporter GLT-1. J. Neurochem. 94, 1180-1188 (2005).
115. Waxman, E. A., Baconguis, I., Lynch, D. R. & Robinson, M. B. N-methyl-D-aspartate receptor-dependent regulation of the glutamate transporter excitatory amino acid carrier 1. J. Biol. Chem. 282, 17594-17607 (2007).
116. Marie, H. et al. The amino terminus of the glial glutamate transporter GLT-1 interacts with the LIM protein Ajuba. Mol. Cell. Neurosci. 19, 152-164 (2002).
117. Levenson, J. et al. Long-term potentiation and contextual fear conditioning increase neuronal glutamate uptake. Nature Neurosci. 5, 155-161 (2002). This study provided the unexpected finding that learning and memory paradigms can rapidly upregulate glutamate-transporter surface expression.
118. Pita-Almenar, J. D., Collado, M. S., Colbert, C. M. & Eskin, A. Different mechanisms exist for the plasticity of glutamate reuptake during early long-term potentiation (LTP) and late LTP. J. Neurosci. 26, 10461-10471 (2006).
119. Genoud, C. et al. Plasticity of astrocytic coverage and glutamate transporter expression in adult mouse cortex. PLoS Biol. 4, e343 (2006).
120. Shen, Y. & Linden, D. J. Long-term potentiation of neuronal glutamate transporters. Neuron 46, 715-722 (2005).
121. Miller, H. P., Levey, A. I., Rothstein, J. D., Tzingounis, A. V. & Conn, P. J. Alterations in glutamate transporter protein levels in kindling-induced epilepsy. J. Neurochem. 68, 1564-1570 (1997).
122. Crino, P. B. et al. Increased expression of the neuronal glutamate transporter (EAAT3/EAAC1) in hippocampal and neocortical epilepsy. Epilepsia 43, 211-218 (2002).
123. Zhang, G., Raol, Y. S., Hsu, F. C. & Brooks-Kayal, A. R. Long-term alterations in glutamate receptor and transporter expression following early-life seizures are associated with increased seizure susceptibility. J. Neurochem. 88, 91-101 (2004).
124. Xu, N. J. et al. Morphine withdrawal increases glutamate uptake and surface expression of glutamate transporter GLT1 at hippocampal synapses. J. Neurosci. 23, 4775-4784 (2003).
125. Tsvetkov, E., Shin, R. M. & Bolshakov, V. Y. Glutamate uptake determines pathway specificity of long-term potentiation in the neural circuitry of fear conditioning. Neuron 41, 139-151 (2004).
126. Asztely, F., Erdemli, G. & Kullmann, D. M. Extrasynaptic glutamate spillover in the hippocampus: dependence on temperature and the role of active glutamate uptake. Neuron 18, 281-293 (1997).
127. Diamond, J. S. & Jahr, C. E. Synaptically released glutamate does not overwhelm transporters on hippocampal astrocytes during high-frequency stimulation. J. Neurophysiol. 83, 2835-2843 (2000).
128. Aoyama, K. et al. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nature Neurosci. 9, 119-126 (2006). This article demonstrated that neuronal transporters serve as a route for cysteine uptake in neurons, possibly preventing neuronal degeneration.
129. Wadiche, J. I. & Kavanaugh, M. P. Macroscopic and microscopic properties of a cloned glutamate transporter/chloride channel. J. Neurosci. 18, 7650-7661 (1998).
130. 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).
131. Bergles, D. E., Tzingounis, A. V. & Jahr, C. E. Comparison of coupled and uncoupled currents during glutamate uptake by GLT-1 transporters. J. Neurosci. 22, 10153-10162 (2002).
132. Larsson, H. P., Tzingounis, A. V., Koch, H. P. & Kavanaugh, M. P. Fluorometric measurements of conformational changes in glutamate transporters. Proc. Natl Acad. Sci. USA 101, 3951-3956 (2004).
133. Picaud, S., Larsson, H. P., Wellis, D. P., Lecar, H. & Werblin, F. Cone photoreceptors respond to their own glutamate release in the tiger salamander. Proc. Natl Acad. Sci. USA 92, 9417-9421 (1995).
134. Eliasof, S. & Jahr, C. E. Retinal glial cell glutamate transporter is coupled to an anionic conductance. Proc. Natl Acad. Sci. USA 93, 4153-4158 (1996).
135. Clark, B. A. & Barbour, B. Currents evoked in Bergmann glial cells by parallel fibre stimulation in rat cerebellar slices. J. Physiol. 502, 335-350 (1997).
136. Bergles, D. E., Dzubay, J. A. & Jahr, C. E. Glutamate transporter currents in bergmann glial cells follow the time course of extrasynaptic glutamate. Proc. Natl Acad. Sci. USA 94, 14821-14825 (1997).
137. Bergles, D. E. & Jahr, C. E. Synaptic activation of glutamate transporters in hippocampal astrocytes. Neuron 19, 1297-1308 (1997).
138. Wadiche, J. I., Tzingounis, A. V. & Jahr, C. E. Intrinsic kinetics determine the time course of neuronal synaptic transporter currents. Proc. Natl Acad. Sci. USA 103, 1083-1087 (2006).
139. Diamond, J. S. Deriving the glutamate clearance time course from transporter currents in CA1 hippocampal astrocytes: transmitter uptake gets faster during development. J. Neurosci. 25, 2906-2916 (2005).
140. Mennerick, S. et al. Substrate turnover by transporters curtails synaptic glutamate transients. J. Neurosci. 19, 9242-9251 (1999).
141. Tzingounis, A. V. Kinetic Mechanism and Modulation of Glutamate Transporters. Thesis, Vollum Institute (2002).
142. 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).
143. 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).
144. Clements, J. D., Lester, R. A., Tong, G., Jahr, C. E. & Westbrook, G. L. The time course of glutamate in the synaptic cleft. Science 258, 1498-1501 (1992).
145. Rusakov, D. A. & Kullmann, D. M. Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake, and receptor activation. J. Neurosci. 18, 3158-3170 (1998).