Molecular Neurobiology

, Volume 26, Issue 2–3, pp 251–268 | Cite as

Mechanisms of GABAA receptor assembly and trafficking

Implications for the modulation of inhibitory neurotransmission
  • Josef T. Kittler
  • Kristina McAinsh
  • Stephen J. Moss
Article

Abstract

Fast synaptic inhibition in the brain is largely mediated by ionotropic GABA receptors, which can be subdivided into GABAA and GABAC receptors based on pharmacological and molecular criteria. GABAA receptors are important therapeutic targets for a range of sedative, anxiolytic, and hypnotic agents and are implicated in several diseases including epilepsy, anxiety, depression, and substance abuse. In addition, modulating the efficacy of GABAergic neurotransmission may play a key role in neuronal plasticity. Recent studies have begun to reveal that the accumulation of ionotropic GABAA receptors at synapses is a highly regulated process that is facilitated by receptor-associated proteins and other cell-signaling molecules. This review focuses on recent experimental evidence detailing the mechanisms that control the assembly and transport of functional ionotropic GABAA receptors to cell surface sites, in addition to their stability at synaptic sites. These regulatory processes will be discussed within the context of the dynamic modulation of synaptic inhibition in the central nervous system (CNS).

Index Entries

Gephyrin PLIC GABARAP assembly endoplasmic reticulum ER targeting inhibitory synapse GABA ion channel endocytosis receptor dynamin NSF AP2 clathrin 

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References

  1. 1.
    Couve, A., Moss, S. J., and Pangalos, M. N. (2000) GABAB receptors: a new paradigm in G protein signaling. Mol. Cell Neurosci. 16(4), 296–312.PubMedCrossRefGoogle Scholar
  2. 2.
    Moss, S. J. and Smart, T. G. (2001) Constructing inhibitory synapses. Nat. Rev. Neurosci. 2(4), 240–250.PubMedCrossRefGoogle Scholar
  3. 3.
    Macdonald, R. L. and Olsen, R. W. (1994) GABAA receptor channels. Annu. Rev. Neurosci. 17, 569–602.PubMedGoogle Scholar
  4. 4.
    Rabow, L. E., Russek, S. J., and Farb, D. H. (1995) From ion currents to genomic analysis: recent advances in GABAA receptor research. Synapse 21(3), 189–274.PubMedCrossRefGoogle Scholar
  5. 5.
    Chandler, L. J., Harris, R. A., and Crews, F. T. (1998) Ethanol tolerance and synaptic plasticity. Trends Pharmacol. Sci. 19(12), 491–495.PubMedCrossRefGoogle Scholar
  6. 6.
    Wallace, R. H., Marini, C., Petrou, S., et al. (2001) Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat. Genet. 28(1), 49–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Baulac, S., Huberfeld, G., Gourfinkel-An, I., et al. (2001) First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat. Genet. 28(1), 46–48.PubMedCrossRefGoogle Scholar
  8. 8.
    Bateson, A. N. (2002) Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal. Curr. Pharm. Des. 8(1), 5–21.PubMedCrossRefGoogle Scholar
  9. 9.
    Ortells, M. O. and Lunt, G. G. (1995) Evolutionary history of the ligand-gated ion-channel superfamily of receptors. Trends Neurosci. 18(3), 121–127.PubMedCrossRefGoogle Scholar
  10. 10.
    Davies, P.A., Hanna, M. C., Hales, T. G., and Kirkness, E. F. (1997) Insensitivity to anaesthetic agents conferred by a class of GABA(A) receptor subunit. Nature 385(6619), 820–823.PubMedCrossRefGoogle Scholar
  11. 11.
    Hedblom, E. and Kirkness, E. F. (1997) A novel class of GABAA receptor subunit in tissues of the reproductive system. J. Biol. Chem. 272(24), 15,346–15,350.CrossRefGoogle Scholar
  12. 12.
    Bormann, J. (2000) The ‘ABC’ of GABA receptors. Trends Pharmacol. Sci. 21(1), 16–19.PubMedCrossRefGoogle Scholar
  13. 13.
    Wisden, W., Laurie, D. J., Monyer, H., and Seeburg, P. H. (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J. Neurosci. 12(3), 1040–1062.PubMedGoogle Scholar
  14. 14.
    Laurie, D. J., Wisden, W., and Seeburg, P. H. (1992) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J. Neurosci. 12(11), 4151–4172PubMedGoogle Scholar
  15. 15.
    Fritschy, J. M. and Mohler, H. (1995) GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359(1), 154–194.PubMedCrossRefGoogle Scholar
  16. 16.
    Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W., and Sperk, G. (2000) GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101(4), 815–850.PubMedCrossRefGoogle Scholar
  17. 17.
    Krishek, B. J., Moss, S. J., and Smart, T. G. (1996) Homomeric beta 1 gamma-aminobutyric acid A receptor-ion channels: evaluation of pharmacological and physiological properties. Mol. Pharmacol. 49(3), 494–504.PubMedGoogle Scholar
  18. 18.
    Davies, P. A., Kirkness, E. F., and Hales, T. G. (1997) Modulation by general anaesthetics of rat GABAA receptors comprised of alpha 1 beta 3 and beta 3 subunits expressed in human embryonic kidney 293 cells. Br. J. Pharmacol. 120(5), 899–909.PubMedCrossRefGoogle Scholar
  19. 19.
    Connolly, C. N., Wooltorton, J. R., Smart, T. G., and Moss, S. J. (1996) Subcellular localization of gamma-aminobutyric acid type A receptors is determined by receptor beta subunits. Proc. Natl. Acad. Sci. USA 93(18), 9899–9904.PubMedCrossRefGoogle Scholar
  20. 20.
    Wooltorton, J. R., Moss, S. J., and Smart, T. G. (1997) Pharmacological and physiological characterization of murine homomeric beta3 GABA(A) receptors. Eur. J. Neurosci. 9(11), 2225–2235.PubMedCrossRefGoogle Scholar
  21. 21.
    Pritchett, D. B., Sontheimer, H., Shivers, B. D., et al. (1989) Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature 338(6216), 582–585.PubMedCrossRefGoogle Scholar
  22. 22.
    Shivers, B. D., Killisch, I., Sprengel, R., et al. (1989) Two novel GABAA receptor subunits exist in distinct neuronal subpopulations. Neuron 3(3), 327–337.PubMedCrossRefGoogle Scholar
  23. 23.
    Connolly, C. N., Krishek, B. J., McDonald, B. J., Smart, T. G., and Moss, S. J. (1996) Assembly and cell surface expression of heteromeric and homomeric gamma- aminobutyric acid type A receptors. J. Biol. Chem. 271(1), 89–96.PubMedCrossRefGoogle Scholar
  24. 24.
    Levitan, E. S., Schofield, P. R., Burt, D. R., et al. (1988) Structural and functional basis for GABAA receptor heterogeneity. Nature 335(6185), 76–79.PubMedCrossRefGoogle Scholar
  25. 25.
    Levitan, E. S., Blair, L. A., Dionne, V. E., and Barnard, E. A. (1988) Biophysical and pharmacological properties of cloned GABAA receptor subunits expressed in Xenopus oocytes. Neuron 1(9), 773–781.PubMedCrossRefGoogle Scholar
  26. 26.
    Schofield, P. R., Darlison, M. G., Fujita, N., et al. (1987) Sequence and functional expression of the GABA A receptor shows a ligandgated receptor super-family. Nature 328(6127), 221–227.PubMedCrossRefGoogle Scholar
  27. 27.
    Draguhn, A., Verdorn, T. A., Ewert, M., Seeburg, P. H., and Sakmann, B. (1990) Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2+. Neuron 5(6), 781–788.PubMedCrossRefGoogle Scholar
  28. 27a.
    Pritchett, D. B., Luddens, H., and Seeburg, P. H. (1989) Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science 245(4924), 1389–1392.PubMedCrossRefGoogle Scholar
  29. 28.
    Tretter, V., Ehya, N., Fuchs, K., and Sieghart, W. (1997) Stoichiometry and assembly of a recombinant GABAA receptor subtype. J. Neurosci. 17(8), 2728–2737PubMedGoogle Scholar
  30. 29.
    Vicini, S., Ferguson, C., Prybylowski, K., Kralic, J., Morrow, A. L., and Homanics, G. E. (2001) GABA(A) receptor alpha1 subunit deletion prevents developmental changes of inhibitory synaptic currents in cerebellar neurons. J. Neurosci. 21(9), 3009–3016.PubMedGoogle Scholar
  31. 30.
    Sur, C., Wafford, K. A., Reynolds, D. S., et al. (2000) Loss of the major GABA(A) receptor subtype in the brain is not lethal in mice. J. Neurosci. 21(10), 3409–3418.Google Scholar
  32. 31.
    Brickley, S. G., Revilla, V., Cull-Candy, S. G., Wisden, W., and Farrant, M. (2001) Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature 409(6816), 88–92.PubMedCrossRefGoogle Scholar
  33. 32.
    Tretter, V., Hauer, B., Nusser, Z., et al. (2001) Targeted disruption of the GABA(A) receptor delta subunit gene leads to an up-regulation of gamma 2 subunit-containing receptors in cerebellar granule cells. J. Biol. Chem. 276(13), 10,532–10,538.CrossRefGoogle Scholar
  34. 32a.
    Homanics, G.E., DeLorey, T.M., Firestone, L. L., et al. (1997) Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Natl. Acad. Sci. USA 94(8), 4143–4148.PubMedCrossRefGoogle Scholar
  35. 32b.
    DeLorey, T.M., Handforth, A., Anagnostaras, S. G., et al. (1998) Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J. Neurosci. 18(20), 8505–8514.PubMedGoogle Scholar
  36. 32c.
    Gunther, U., Benson, J., Benke, D., et al. (1995) Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. Synaptic control of glycine and GABA(A) receptors and gephyrin expression in cultured motoneurons. Proc. Natl. Acad. Sci. USA 92(17), 7749–7753.PubMedCrossRefGoogle Scholar
  37. 33.
    Saxena, N. C. and Macdonald, R. L. (1996) Properties of putative cerebellar gammaaminobutyric acid A receptor isoforms. Mol. Pharmacol. 49(3), 567–579.PubMedGoogle Scholar
  38. 34.
    Saxena, N. C. and Macdonald, R. L. (1994) Assembly of GABAA receptor subunits: role of the delta subunit. J. Neurosci. 14(11 Pt 2), 7077–7086.PubMedGoogle Scholar
  39. 35.
    Margeta-Mitrovic, M., Jan, Y. N., and Jan, L. Y. (2000) A trafficking checkpoint controls GABA(B) receptor heterodimerization. Neuron 27(1), 97–106.PubMedCrossRefGoogle Scholar
  40. 36.
    Green, W. N. and Millar, N. S. (1995) Ion-channel assembly. Trends Neurosci. 18(6), 280–287.PubMedCrossRefGoogle Scholar
  41. 37.
    Couve, A., Filippov, A. K., Connolly, C. N., Bettler, B., Brown, D. A., and Moss, S. J. (1998) Intracellular retention of recombinant GABAB receptors. J. Biol. Chem. 273(41), 26,361–26,367.CrossRefGoogle Scholar
  42. 38.
    Standley, S., Roche, K. W., McCallum, J., Sans, N., and Wenthold, R. J. (2000) PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron 28(3), 887–898.PubMedCrossRefGoogle Scholar
  43. 39.
    Angelotti, T. P. and Macdonald, R. L. (1993) Assembly of GABAA receptor subunits: alpha 1 beta 1 and alpha 1 beta 1 gamma 2S subunits produce unique ion channels with dissimilar single- channel properties. J. Neurosci. 13(4), 1429–1440.PubMedGoogle Scholar
  44. 40.
    Taylor, P. M., Connolly, C. N., Kittler, J. T., et al. (2000) Identification of residues within GABA(A) receptor alpha subunits that mediate specific assembly with receptor beta subunits. J. Neurosci. 20(4), 1297–1306.PubMedGoogle Scholar
  45. 41.
    Connolly, C. N., Uren, J. M., Thomas, P., et al. (1999) Subcellular localization and endocytosis of homomeric gamma2 subunit splice variants of gamma-aminobutyric acid type A receptors. Mol. Cell Neurosci. 13(4), 259–271.PubMedCrossRefGoogle Scholar
  46. 42.
    Gorrie, G. H., Vallis, Y., Stephenson, A., et al. (1997) Assembly of GABAA receptors composed of alpha1 and beta2 subunits in both cultured neurons and fibroblasts. J. Neurosci. 17(17), 6587–6596.PubMedGoogle Scholar
  47. 43.
    Hammond, C. and Helenius, A. (1994) Folding of VSV G protein: sequential interaction with BiP and calnexin. Science 266(5184), 456–458.PubMedCrossRefGoogle Scholar
  48. 44.
    Whiting, P., McKernan, R. M., and Iversen, L. L. (1990) Another mechanism for creating diversity in gamma-aminobutyrate type A receptors: RNA splicing directs expression of two forms of gamma 2 phosphorylation site. Proc. Natl. Acad. Sci. USA 87(24), 9966–9970.PubMedCrossRefGoogle Scholar
  49. 45.
    Kofuji, P., Wang, J. B., Moss, S. J., Huganir, R. L., and Burt, D. R. (1991) Generation of two forms of the gamma-aminobutyric acidA receptor gamma 2-subunit in mice by alternative splicing. J. Neurochem. 56(2), 713–715.PubMedCrossRefGoogle Scholar
  50. 46.
    Connolly, C. N., Kittler, J. T., Thomas, P., et al. (1999) Cell surface stability of gamma-aminobutyric acid type A receptors. Dependence on protein kinase C activity and subunit composition. J. Biol. Chem. 274(51), 36,565–13,572.CrossRefGoogle Scholar
  51. 47.
    Kittler, J. T., Wang, J., Connolly, C. N., Vicini, S., Smart, T. G., and Moss, S. J. (2000) Analysis of GABAA receptor assembly in mammalian cell lines and hippocampal neurons using gamma 2 subunit green fluorescent protein chimeras. Mol. Cell Neurosci. 16(4), 440–452.PubMedCrossRefGoogle Scholar
  52. 48.
    Taylor, P. M., Thomas, P., Gorrie, G. H., et al. (1999) Identification of amino acid residues within GABA(A) receptor beta subunits that mediate both homomeric and heteromeric receptor expression. J. Neurosci. 19(15), 6360–6371.PubMedGoogle Scholar
  53. 49.
    Gardiol, A., Racca, C., and Triller, A. (1999) Dendritic and postsynaptic protein synthetic machinery. J. Neurosci. 19(1), 168–179.PubMedGoogle Scholar
  54. 50.
    Racca, C., Gardiol, A., and Triller, A. (1997) Dendritic and postsynaptic localizations of glycine receptor alpha subunit mRNAs. J. Neurosci. 17(5), 1691–1700.PubMedGoogle Scholar
  55. 51.
    Klausberger, T., Fuchs, K., Mayer, B., Ehya, N., and Sieghart, W. (2000) GABA(A) receptor assembly. Identification and structure of gamma(2) sequences forming the intersubunit contacts with alpha(1) and beta(3) subunits. J. Biol. Chem. 275(12), 8921–8928.PubMedCrossRefGoogle Scholar
  56. 52.
    Klausberger, T., Ehya, N., Fuchs, K., Fuchs, T., Ebert, V., Sarto, I., and sieghart, W. (2001) Detection and binding properties of GABA(A) receptor assembly intermediates. J. Biol. Chem. 276(19), 16,024–16,032.CrossRefGoogle Scholar
  57. 53.
    Klausberger, T., Sarto, I., Ehya, N., et al. (2001) Alternate use of distinct intersubunit contacts controls GABAA receptor assembly and stoichiometry. J. Neurosci. 21(23), 9124–9133.PubMedGoogle Scholar
  58. 54.
    Srinivasan, S., Nichols, C. J., Lawless, G. M., Olsen, R. W., and Tobin, A. J. (1999) Two invariant tryptophans on the alphal subunit define domains necessary for GABA(A) receptor assembly. J. Biol. Chem. 274(38), 26,633–26,638.CrossRefGoogle Scholar
  59. 55.
    Smith, G. B. and Olsen, R. W. (1994) Identification of a [3H]muscimol photoaffinity substrate in the bovine gamma-aminobutyric acidA receptor alpha subunit. J. Biol. Chem. 269(32), 20,380–20,387.Google Scholar
  60. 56.
    Rudolph, U., Crestani, F., Benke, D., et al. (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401(6755), 796–800.PubMedCrossRefGoogle Scholar
  61. 57.
    Rudolph, U., Crestani, F., and Mohler, H. (2001) GABA(A) receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol. Sci. 22(4), 188–194.PubMedCrossRefGoogle Scholar
  62. 58.
    Nusser, Z., Sieghart, W., Benke, D., Fritschy, J. M., and Somogyi, P. (1996) Differential synaptic localization of two major gamma-aminobutyric acid type A receptor alpha subunits on hippocampal pyramidal cells. Proc. Natl. Acad. Sci. USA 93(21), 11,939–11,944.CrossRefGoogle Scholar
  63. 59.
    Fritschy, J. M., Johnson, D. K., Mohler, H., and Rudolph, U. (1998) Independent assembly and subcellular targeting of GABA(A)-receptor subtypes demonstrated in mouse hippocampal and olfactory neurons in vivo. Neurosci. Lett. 249(2–3), 99–102.PubMedCrossRefGoogle Scholar
  64. 60.
    Koulen, P., Sassoe-Pognetto, M., Grunert, U., and Wassle, H. (1996) Selective clustering of GABA(A) and glycine receptors in the mammalian retina. J. Neurosci. 16(6), 2127–2140.PubMedGoogle Scholar
  65. 61.
    Nusser, Z., Sieghart, W., Stephenson, F. A., and Somogyi, P. (1996) The alpha 6 subunit of the GABAA receptor is concentrated in both inhibitory and excitatory synapses on cerebellar granule cells. J. Neurosci. 16(1), 103–114.PubMedGoogle Scholar
  66. 62.
    Nusser, Z., Sieghart, W., and Somogyi, P. (1998) Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci. 18(5), 1693–1703.PubMedGoogle Scholar
  67. 63.
    Brickley, S. G., Cull-Candy, S. G., and Farrant, M. (1999) Single-channel properties of synaptic and extrasynaptic GABAA receptors suggest differential targeting of receptor subtypes. J. Neurosci. 19(8), 2960–2973.PubMedGoogle Scholar
  68. 64.
    Banks, M. I. and Pearce, R. A. (2000) Kinetic differences between synaptic and extrasynaptic GABA(A) receptors in CA1 pyramidal cells. J. Neurosci. 20(3), 937–948.PubMedGoogle Scholar
  69. 65.
    Brickley, S. G., Cull-Candy, S. G., and Farrant, M. (1996) Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J. Physiol. (Lond.) 497(Pt 3), 753–759.Google Scholar
  70. 66.
    Wall, M. J. and Usowicz, M. M. (1997) Development of action potential-dependent and independent spontaneous GABAA receptor-mediated currents in granule cells of postnatal rat cerebellum. Eur. J. Neurosci. 9(3), 533–548.PubMedCrossRefGoogle Scholar
  71. 67.
    Rossi, D. J. and Hamann, M. (1998) Spillover-mediated transmission at inhibitory synapses promoted by high affinity alpha6 subunit GABA(A) receptors and glomerular geometry [published erratum appears in Neuron 1998 July, 21(1), 527].Google Scholar
  72. 68.
    Jones, A., Korpi, E. R., McKernan, R. M., et al. (1997) Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression. J. Neurosci. 17(4), 1350–1362.PubMedGoogle Scholar
  73. 69.
    Hamann, M., Rossi, D. J., and Attwell, D. (2002) Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex. Neuron 33(4), 625–633.PubMedCrossRefGoogle Scholar
  74. 70.
    Jessell, T. M. and Kandel, E. R. (1993) Synaptic transmission: a bidirectional and self-modifiable form of cell- cell communication. Cell 72(Suppl), 1–30.PubMedCrossRefGoogle Scholar
  75. 71.
    Bliss, T. V. and Collingridge, G. L. (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361(6407), 31–39.PubMedCrossRefGoogle Scholar
  76. 72.
    Busch, C. and Sakmann, B. (1990) Synaptic transmission in hippocampal neurons: numerical reconstruction of quantal IPSCs. Cold Spring Harb. Symp. Quant. Biol. 55, 69–80.PubMedGoogle Scholar
  77. 73.
    Redman, S. (1990) Quantal analysis of synaptic potentials in neurons of the central nervous system. Physiol. Rev. 70(1), 165–198.PubMedGoogle Scholar
  78. 74.
    Tong, G. and Jahr, C. E. (1994) Multivesicular release from excitatory synapses of cultured hippocampal neurons. Neuron 12(1), 51–59.PubMedCrossRefGoogle Scholar
  79. 75.
    Edwards, F. A. (1995) Anatomy and electrophysiology of fast central synapses lead to a structural model for long-term potentiation. Physiol. Rev. 75(4), 759–787.PubMedGoogle Scholar
  80. 76.
    Mody, I., De Koninck, Y., Otis, T. S., and Soltesz, I. (1994) Bridging the cleft at GABA synapses in the brain. Trends Neurosci. 17(12), 517–525.PubMedCrossRefGoogle Scholar
  81. 77.
    Nusser, Z., Cull-Candy, S., and Farrant, M. (1997) Differences in synaptic GABA(A) receptor number underlie variation in GABA mini amplitude. Neuron 19(3), 697–709.PubMedCrossRefGoogle Scholar
  82. 78.
    Nusser, Z., Hajos, N., Somogyi, P., and Mody, I. (1998) Increased number of synaptic GABA(A) receptors underlies potentiation at hippocampal inhibitory synapses. Nature 395(6698), 172–177.PubMedCrossRefGoogle Scholar
  83. 79.
    Otis, T. S., De Koninck, Y., and Mody, I. (1994) Lasting potentiation of inhibition is associated with an increased number of gamma-aminobutyric acid type A receptors activated during miniature inhibitory postsynaptic currents. Proc. Natl. Acad. Sci. USA 91(16), 7698–7702.PubMedCrossRefGoogle Scholar
  84. 80.
    Wan, Q., Xiong, Z. C., Man, H. Y., et al. (1997) Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388(6643), 686–690.PubMedCrossRefGoogle Scholar
  85. 81.
    Brunig, I., Penschuck, S., Berninger, B., Benson, J., and Fritschy, J. M. (2001) BDNF reduces miniature inhibitory postsynaptic currents by rapid downregulation of GABA(A) receptor surface expression. Eur. J. Neurosci. 13(7), 1320–1328.PubMedCrossRefGoogle Scholar
  86. 82.
    Kittler, J. T., Delmas, P., Jovanovic, J. N., Brown, D. A., Smart, T. G., and Moss, S. J. (2000) Constitutive endocytosis of GABAA receptors by an association with the adaptin AP2 complex modulates inhibitory synaptic currents in hippocampal neurons. J. Neurosci. 20(21), 7972–7977.PubMedGoogle Scholar
  87. 83.
    Chu, P., Murray, S., Lissin, D., and von Zastrow, M. (1997) Delta and kappa opioid receptors are differentially regulated by dynamin-dependent endocytosis when activated by the same alkaloid agonist. J. Biol. Chem. 272(43), 27,124–27,130.CrossRefGoogle Scholar
  88. 84.
    Pitcher, J. A., Freedman, N. J., and Lefkowitz, R. J. (1998) G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653–692.PubMedCrossRefGoogle Scholar
  89. 85.
    Carroll, R. C., Beattie, E. C., Xia, H., et al. (1999) Dynamin-dependent endocytosis of ionotropic glutamate receptors. Proc. Natl. Acad. Sci. USA 96(24), 14,112–14,117.CrossRefGoogle Scholar
  90. 86.
    Carroll, R. C., Beattie, E. C., von Zastrow, M., and Malenka, R. C. (2001) Role of AMPA receptor endocytosis in synaptic plasticity. Nat. Rev. Neurosci. 2(5), 315–324.PubMedCrossRefGoogle Scholar
  91. 87.
    Luscher, C., Xia, H., Beattie, E. C., et al. (1999) Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24(3), 649–658.PubMedCrossRefGoogle Scholar
  92. 88.
    Man, H. Y., Lin, J. W., Ju, W. H., et al. (2000) Regulation of AMPA receptor-mediated synaptic transmission by clathrin- dependent receptor internalization. Neuron 25(3), 649–662.PubMedCrossRefGoogle Scholar
  93. 89.
    Marsh, M. and McMahon, H. T. (1999) The structural era of endocytosis. Science 285(5425), 215–220.PubMedCrossRefGoogle Scholar
  94. 90.
    Tehrani, M. H. and Barnes, E. M., Jr. (1993) Identification of GABAA/benzodiazepine receptors on clathrin-coated vesicles from rat brain. J. Neurochem. 60(5), 1755–1761.PubMedCrossRefGoogle Scholar
  95. 91.
    Tehrani, M. H., Baumgartner, B. J., and Barnes, E. M., Jr. (1997) Clathrin-coated vesicles from bovine brain contain uncoupled GABAA receptors. Brain Res. 776(1–2), 195–203.PubMedCrossRefGoogle Scholar
  96. 92.
    Tehrani, M. H. and Barnes, E. M., Jr. (1997) Sequestration of gamma-aminobutyric acid A receptors on clathrin-coated vesicles during chronic benzodiazepine administration in vivo. J. Pharmacol. Exp. Ther. 283(1), 384–390.PubMedGoogle Scholar
  97. 93.
    Tehrani, M. H. and Barnes, E. M., Jr. (1991) Agonist-dependent internalization of gamma-aminobutyric acid A/benzodiazepine receptors in chick cortical neurons. J. Neurochem. 57(4), 1307–1312.PubMedCrossRefGoogle Scholar
  98. 94.
    Essrich, C., Lorez, M., Benson, J. A., Fritschy, J. M., and Luscher, B. (1998) Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin. Nat. Neurosci. 1(7), 563–571.PubMedCrossRefGoogle Scholar
  99. 95.
    Crestani, F., Lorez, M., Baer, K., et al. (1999) Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat. Neurosci. 2(9), 833–839.PubMedCrossRefGoogle Scholar
  100. 96.
    Kneussel, M. and Betz, H. (2000) Clustering of inhibitory neurotransmitter receptors at developing postsynaptic sites: the membrane activation model. Trends Neurosci. 23(9), 429–435.PubMedCrossRefGoogle Scholar
  101. 97.
    Kittler, J. T. and Moss, S. J. (2001) Neurotransmitter receptor trafficking and the regulation of synaptic strength. Traffic 2(7), 437–448.PubMedCrossRefGoogle Scholar
  102. 98.
    Kneussel, M., Brandstatter, J. H., Laube, B., Stahl, S., Muller, U., and Betz, H. (1999) Loss of postsynaptic GABA(A) receptor clustering in gephyrin-deficient mice. J. Neurosci. 19(21), 9289–9297.PubMedGoogle Scholar
  103. 98a.
    Levi, S., Chesnoy-Marchais, D., Sieghart, W., and Triller, A. (1999) Synaptic control of glycine and GABA(A) receptors and gephyrin expression in cultured motoneurons. J. Neurosci. 19(17), 7434–7449.PubMedGoogle Scholar
  104. 98b.
    Campos, M. L., de Cabo, C., Wisden, W., Juiz, J. M., and Merlo, D. (2001) Expression of GABA(A) receptor subunits in rat brainstem auditory pathways: cochlear nuclei, superior olivary complex and nucleus of the lateral lemniscus. Neuroscience 102(3), 625–638.PubMedCrossRefGoogle Scholar
  105. 99.
    Wang, H., Bedford, F. K., Brandon, N. J., Moss, S. J., and Olsen, R. W. (1999) GABA(A)-receptor-associated protein links GABA(A) receptors and the cytoskeleton. Nature 397(6714), 69–72.PubMedCrossRefGoogle Scholar
  106. 100.
    Hanley, J. G., Koulen, P., Bedford, F., Gordon-Weeks, P. R., and Moss, S. J. (1999) The protein MAP-1B links GABA(C) receptors to the cytoskeleton at retinal synapses. Nature 397(6714), 66–69.PubMedCrossRefGoogle Scholar
  107. 101.
    Bedford, F. K., Kittler, J. T., Muller, E., et al. (2001) GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1. Nat. Neurosci. 4(9), 908–916.PubMedCrossRefGoogle Scholar
  108. 101a.
    Kins, S., Betz, H., and Kirsch, J. (2000) Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin. Nat. Neurosci. 3(1), 22–29.PubMedCrossRefGoogle Scholar
  109. 101b.
    Mammoto, A., Sasaki, T., Asakura, T., et al. (1998) Interactions of drebrin and gephyrin with profilin. Biochem. Biophys. Res. Commun. 243(1), 86–89.PubMedCrossRefGoogle Scholar
  110. 102.
    Nymann-Andersen, J., Wang, H., Chen, L., Kittler, J. T., Moss, S. J., and Olsen, R. W. (2002) Subunit specificity and interaction domain between GABA(A) receptor- associated protein (GABARAP) and GABA(A) receptors. J. Neurochem. 80(5), 815–823.PubMedCrossRefGoogle Scholar
  111. 103.
    Ohsumi, Y. (2001) Molecular dissection of autophagy: two ubiquitin-like systems. Nat. Rev. Mol. Cell Biol. 2(3), 211–216.PubMedCrossRefGoogle Scholar
  112. 104.
    Sagiv, Y., Legesse-Miller, A., Porat, A., and Elazar, Z. (2000) GATE-16, a membrane transport modulator, interacts with NSF and the Golgi v-SNARE GOS-28. Embo. J. 19(7), 1494–1504.PubMedCrossRefGoogle Scholar
  113. 105.
    Kittler, J. T., Rostaing, P., Schiavo, G., Fritschy, J. M., Olsen, R., Triller, A., and Moss, S. J. (2001) The subcellular distribution of GABARAP and its ability to interact with NSF suggest a role for this protein in the intracellular transport of GABA(A) receptors. Mol. Cell Neurosci. 18(1), 13–25.PubMedCrossRefGoogle Scholar
  114. 106.
    Kabeya, Y., Mizushima, N., Ueno, T., et al. (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. Embo. J. 19(21), 5720–5728.PubMedCrossRefGoogle Scholar
  115. 107.
    Wang, H. and Olsen, R. W. (2000) Binding of the GABA(A) receptor-associated protein (GABARAP) to microtubules and microfilaments suggests involvement of the cytoskeleton in GABARAPGABA(A) receptor interaction. J. Neurochem. 75(2), 644–655.PubMedCrossRefGoogle Scholar
  116. 108.
    Coyle, J. E., Qamar, S., Rajashankar, K. R., and Nikolov, D. B. (2002) Structure of GABARAP in two conformations: implications for GABA(A) receptor localization and tubulin binding. Neuron 33(1), 63–74.PubMedCrossRefGoogle Scholar
  117. 109.
    Chen, L., Wang, H., Vicini, S., and Olsen, R. W. (2000) The gamma-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) promotes GABAA receptor clustering and modulates the channel kinetics. Proc. Natl. Acad. Sci. USA 97(21), 11,557–11,562.Google Scholar
  118. 110.
    Kneussel, M., Haverkamp, S., Fuhrmann, J. C., Wang, H., Wassle, H., Olsen, R. W., and Betz, H. (2000) The gamma-aminobutyric acid type A receptor (GABAAR)-associated protein GABARAP interacts with gephyrin but is not involved in receptor anchoring at the synapse. Proc. Natl. Acad. Sci. USA 97(15), 8594–8599.PubMedCrossRefGoogle Scholar
  119. 111.
    Passafaro, M. and Sheng, M. (1999) Synaptogenesis: The MAP location of GABA receptors Curr. Biol. 9(7), R261-R263.PubMedCrossRefGoogle Scholar
  120. 112.
    Knight, D., Harris, R., McAlister, M. S., et al. (2002) The X-ray crystal structure and putative ligand-derived peptide binding properties of gamma-aminobutyric acid receptor type A receptor-associated protein. J. Biol. Chem. 277(7), 5556–5561.PubMedCrossRefGoogle Scholar
  121. 113.
    Phillips, W. D. and Froehner, S. C. (2002) GABARAP and GABA(A) receptor clustering. Neuron 33(1), 4–6.PubMedCrossRefGoogle Scholar
  122. 114.
    Kanematsu, T., Jang, I. S., Yamaguchi, T., et al. (2002) Role of the PLC-related, catalytically inactive protein p130 in GABA(A) receptor function. Embo. J. 21(5), 1004–1011.PubMedCrossRefGoogle Scholar
  123. 115.
    Wu, A. L., Wang, J., Zheleznyak, A., and Brown, E. J. (1999) Ubiquitin-related proteins regulate interaction of vimentin intermediate filaments with the plasma membrane. Mol. Cell. 4(4), 619–625.PubMedCrossRefGoogle Scholar
  124. 116.
    Luscher, B. and Keller, C. A. (2001) Ubiquitination, proteasomes and GABA(A) receptors. Nat. Cell. Biol. 3(10), E232-E233.PubMedCrossRefGoogle Scholar
  125. 117.
    Mah, A. L., Perry, G., Smith, M. A., and Monteiro, M. J. (2000) Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. J. Cell. Biol. 151(4), 847–862.PubMedCrossRefGoogle Scholar
  126. 118.
    Kleijnen, M. F., Shih, A. H., Zhou, P., Kumar, S., Soccio, R. E., Kedersha, N. L., Gill, G., and Howley, P. M. (2000) The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Mol. Cell. 6(2), 409–419.PubMedCrossRefGoogle Scholar
  127. 119.
    Caillard, O., Ben-Ari, Y., and Gaiarsa, J. L. (1999) Mechanisms of induction and expression of long-term depression at GABAergic synapses in the neonatal rat hippocampus. J. Neurosci. 19(17), 7568–7577.PubMedGoogle Scholar
  128. 120.
    Caillard, O., Ben-Ari, Y., and Gaiarsa, J. L. (1999) Long-term potentiation of GABAergic synaptic transmission in neonatal rat hippocampus. J. Physiol. (Lond.) 518(Pt 1), 109–119.CrossRefGoogle Scholar
  129. 121.
    Kano, M. (1995) Plasticity of inhibitory synapses in the brain: a possible memory mechanism that has been overlooked. Neurosci. Res. 21(3), 177–182.PubMedCrossRefGoogle Scholar
  130. 122.
    Lu, Y. M., Mansuy, I. M., Kandel, E. R., and Roder, J. (2000) Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP. Neuron 26(1), 197–205.PubMedCrossRefGoogle Scholar
  131. 123.
    Luscher, C. and Frerking, M. (2001) Restless AMPA receptors: implications for synaptic transmission and plasticity. Trends Neurosci. 24(11), 665–670.PubMedCrossRefGoogle Scholar
  132. 124.
    Hyman, S. E. and Malenka, R. C. (2001) Addiction and the brain: the neurobiology of compulsion and its persistence. Nat. Rev. Neurosci. 2(10), 695–703.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  • Josef T. Kittler
    • 1
  • Kristina McAinsh
    • 1
  • Stephen J. Moss
    • 1
  1. 1.Medical Research Council Laboratory of Molecular Cell Biology and Department of PharmacologyUniversity College LondonLondonUnited Kingdom

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