Diversity in Structure, Pharmacology, and Regulation of GABAA Receptors

  • H. Möhler
  • D. Benke
  • J. Benson
  • B. Lüscher
  • U. Rudolph
  • J. M. Fritschy
Part of the The Receptors book series (REC)

Abstract

As the main inhibitory neurotransmitter in the brain, GABA is essential for the overall balance between neuronal excitation and inhibition. By acting on GABAA receptors, which are ligand-gated chloride channels, GABA mediates the principal fast inhibitory synaptic transmission. GABA exerts a ubiquitous influence largely by local feedback and feedforward circuits affecting a multitude of CNS functions. Adaptation of GABA-ergic transmission to various biological requirements, in particular to developmental maturation and cell-type specific signal transmission, is achieved by the expression of a multitude of structurally distinct GABAA receptors in the vertebrate brain. Receptor heterogeneity arises from a repertoire of at least 17 subunits, which can be grouped by the degree of sequence homology into 6α, 4β, 4γ, 1δ, and 2ρ subunits. The combinatorial assembly of these subunits (and splice variants of several of them) into a presumably pentameric heterooligomeric structure results in diverse receptor subtypes (for review, see Barnard, 1995; Luddens et al., 1995; Möhler et al., 1995a,b; Sieghart, 1995; Smith and Olsen, 1995). The most prevalent types of GABAA receptors have recently been identified and allocated to particular neuronal circuits. Apart from the physiological role in neuron-specific signal transduction (Table 1), GABAA receptor heterogeneity is of major pharmacological relevance. Many neuroactive drugs act on GABAA receptors, in particular ligands of the benzodiazepine (BZ) site, which are in clinical use for the treatment of anxiety, insomnia, muscle spasms, and epilepsy.

Keywords

Receptor Subtype GABAA Receptor Receptor Subunit Partial Agonist Angelman Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Amin, J. and Weiss, D. S. (1993) GABAA receptor needs two homologous domains of the β-subunit for activation by GABA but not by pentobarbital. Nature 366 565–567.Google Scholar
  2. Angelman, H. (1965) ‘Puppet’ children. Dev. Med. Child Neurol 7 681–683.Google Scholar
  3. Auta, J., Giusti, P., Guidotti, A., and Costa, E. (1994) Imidazenil, a partial positive allosteric modulator of GABAA receptors, exhibits low tolerance and dependence liabilities in the rat. J. Pharmacol. Exp. Ther 270, 1262–1269.Google Scholar
  4. Backus, K. H., Arigoni, M., Drescher, U., Scheurer, L., Malherbe, P., Möhler, H., and Benson, J. A. (1993) Stoichiometry of a recombinant GABAA-receptor deduced from mutation-induced rectification. Neuroreport 5, 285–288.Google Scholar
  5. Barnard, E. A. (1995) The molecular biology of GABAA receptors and their structural determinants, in GABA A Receptors and Anxiety. From Neurobiology to Treatment, Advances in Biochemical Psychoparmacology, vol. 48 ( Biggio, G., Sanna, E., Serra, M., and Costa, E., eds.), Raven, New York, pp. 1–16.Google Scholar
  6. Bell, M. V., Bloomfield, J., McKinley, M., Patterson, M. N., Darlison, M. G., Barnard, E. A., and Davies, K. E. (1989) Physical linkage of a GABAA receptor subunit gene to the DXS374 locus in human Xq28. Am. J. Hum. Genet 45, 883–888.PubMedGoogle Scholar
  7. Benke, D., Fritschy, J. M., Trzeciak, A., Bannwarth, W., and Möhler, H (1994) Distribution, prevalence and drug-binding profile of GABAA-receptors subtypes differing in 13-subunit isoform. J Biol. Chem 269 27,100–27,107.Google Scholar
  8. Benke, D., Mertens, S., Trzeciak, A., Gillessen, D., and Möhler, H. (1991) GABAA receptors display association of y2-subunit with al-and (3213 subunits. J. Biol. Chem 266, 4478–4483.Google Scholar
  9. Benke, D., Honer, M., Michel, C., and Mohler, H. (1996) GABAA-receptor subtypes differentiated by their y-subunit variants: prevalence, pharmacology and subunit architecture. Neuropharmacol (in press).Google Scholar
  10. Berninger, B., Marty, S., Zafra, F., Berzaghi, M. P., Thoenen, H., and Lindholm, D. (1995) GABAergic stimulation switches from enhancing to repressing BDNF expression in rat hippocampal neurons during maturation in vitro. Development 121, 2327–2335.PubMedGoogle Scholar
  11. Betz, H. (1990) Ligand-gated ion channels in the brain: the amino acid receptor super-family. Neuron 5, 383–392.PubMedCrossRefGoogle Scholar
  12. Bohlhalter, S., Weinmann, O., Möhler, H., and Fritschy, J. M. (1996) Laminar compartment- alization of GABAA-receptor subtypes in the spinal cord. J. Neurosci.16, 283–297.Google Scholar
  13. Browning, M. D., Bureau, M., Dudek, E. M., and Olsen, R. W. (1990) Protein kinase C and cAMP-dependent protein kinase phosphorylate the ß subunit of the purified y-aminobutyric acid A receptor. Proc. Natl. Acad. Sci. USA 87, 1315–1318.PubMedCrossRefGoogle Scholar
  14. Buckle, V. J., Fujita, N., Ryder-Cook, A., Derry, J. M. J., Barnard, R. J., Lebo, R. V., Schofield, P. R., Seeburg, P. H., Bateson, A. N., Darlison, M. G., and Barnard, E. A. (1989) Chromosomal localization of GABAA receptor subunit genes: relationship to human genetic disease. Neuron 3, 647–654.PubMedCrossRefGoogle Scholar
  15. Busto, U., Kaplan, H. L., Zawertailo, L., and Sellers, E. M. (1994) Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans. Clin. Pharmacol. Ther 55, 451–463.PubMedCrossRefGoogle Scholar
  16. Clark, M., Massenburg, G. S., Weiss, S. R. B., and Post, R. M. (1994) Analysis of the hippocampal GABAA receptor system in kindled rats by autoradiographic and in situ hybridization techniques: contingent tolerance to carbamazepine. Mol. Brain. Res 26, 309–319.PubMedCrossRefGoogle Scholar
  17. Costa, E., Auta, J., Caruncho, H., Guidotti, A., Impagnatiello, F., Pesold, C., and Thompson, D. M. (1995) A search for a new anticonvulsant and anxiolytic benzodiazepine devoid of side effects and tolerance liability, in GABA A Receptors and Anxiety. From Neurobiology to Treatment, Advances in Biochemical Psychopharmacology, vol. 48 ( Biggio, G., Sanna, E., Serra, M., and Costa, E., eds.), Raven, New York, pp. 75–92.Google Scholar
  18. Culiat, C. T., Stubbs, L. J., Montgomery, C. S., Russell, L. B., and Rinchik, E. M. (1994) Phenotypic consequences of deletion of the y3, a5, or ß3 subunit of the type A y-aminobutyric acid receptor in mice. Proc. Natl. Acad. Sci. USA 91, 2815–2818.PubMedCrossRefGoogle Scholar
  19. Culiat, C. T., Stubbs, L., Nicholls, R. D., Montgomery, C. S., Russell, L. B., Johnson, D. K., and Rinchik, E. M. (1993) Concordance between isolated cleft palate in mice and alterations within a region including the gene encoding the 133 subunit of the type A y-aminobutyric acid receptor. Proc. Natl. Acad. Sci. USA 90, 5105–5109.PubMedCrossRefGoogle Scholar
  20. Culiat, C. T., Stubbs, L., Woychik, R. P., Russell, L. B., Johnson, D. K., and Riuchik, E. M. (1995) Deficiency of the 03-subunit of the type A y-aminobutyric acid receptor causes cleft palate in mice. Nature Genet. 11, 344–346.PubMedCrossRefGoogle Scholar
  21. Ducic, I., Puia, G., Vicini, S., and Costa, E. (1993) Triazolam is more efficacious than diazepam in a broad spectrum of recombinant receptors. Eur. J. Pharmacol 244, 29–35.PubMedCrossRefGoogle Scholar
  22. Duggan, M. J., Pollard, S., and Stephenson, F. A. (1991) Immunoaffinity purification of GABAA receptor a-subunit iso-oligomers. Demonstration of receptor populations containing ala2, ala3, and a2a3 subunit pairs. J. Biol. Chem. 266, 24,778–24, 784.Google Scholar
  23. Duggan, M. J., Pollard, S., and Stephenson, F. A. (1992) Quantitative immunoprecipitation studies with anti-y-aminobutyric acidA receptor y2 1–15 cys antibodies. J. Neurochem 58, 72–77.PubMedCrossRefGoogle Scholar
  24. Duka, T., Krause, W., Dorow, R., Rohloff, A., Hott, H., and Voet B. (1993) Abecarnil, a new ß-carboline anxiolytic: preliminary clinical pharmacology, in Anxiolytic /3-Carbolines ( Stephens, D. N., ed.), Springer-Verlag, Berlin, pp. 132–148.CrossRefGoogle Scholar
  25. During, M. J., Ryder, K. M., and Spencer, D. D. (1995) Hippocampal GABA transporter function in temporal-lobe epilepsy. Nature 376, 174–177.PubMedCrossRefGoogle Scholar
  26. During, M. J. and Spencer, D. D. (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341, 1607–1610.PubMedCrossRefGoogle Scholar
  27. Endö, S. and Olsen, R. W. (1993) Antibodies specific for a-subunit subtypes of GABAA receptors reveal brain regional heterogeneity. J. Neurochem 60, 1388–1398.PubMedCrossRefGoogle Scholar
  28. Enz, R., Brandstatter, J. H., Hartveit, E., Wassle, H., and Bormann, J. (1995) Expression of GABA receptor p 1 and p2 subunits in the retina and brain of the rat. Eur. J. Neurosci 7, 1495–1501.PubMedCrossRefGoogle Scholar
  29. Faull, R. L. M., Waldvogel, H. J., Nicholson, L. F. B., and Synek, B. J. L. (1993) The distribution of GABAA-benzodiazepine receptors in the basal ganglia in Huntington’s disease and in the quinolinic acid-lesioned rat. Prog. Brain Res 99, 105–123.Google Scholar
  30. ffrench-Constant, R. H., Steichen, J. C., Rocheleau, T. A., Aronstein, K., and Roush, R. T. (1993) A single-amino acid substitution in a y-aminobutyric acid subtype A receptor locus is associated with cyclodiene insecticide resistance in Drosophila populations. Proc. Natl. Acad. Sci. USA 90, 1957–1961.Google Scholar
  31. Fritschy, J. M. and Möhler, H. (1995) GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol 359, 154–194.PubMedCrossRefGoogle Scholar
  32. Fritschy, J. M., Benke, D., Mertens, S., Gao, B., and Möhler, H. (1993) Immunochemical distinction of GABAA-receptor subtypes differing in drug binding profiles and cellular distribution. Soc. Neurosci. Abstracts 19, 476.Google Scholar
  33. Fritschy, J. M., Benke, D., Mertens, S., Oertel, W. H., Bachi, T., and Möhler, H. (1992) Five subtypes of type A y-aminobutyric acid receptors identified in neurons by double and triple immunofluorescence staining with subunit-specific antibodies. Proc. Natl. Acad. Sci. USA 89, 6726–6730.Google Scholar
  34. Fritschy, J. M., Paysan, J., Enna, A., and Möhler, H. (1994) Switch in the expression of rat GABAA-receptor subtypes during postnatal development: an immunohistochemical study. J. Neurosci 14, 5302–5324.PubMedGoogle Scholar
  35. Gale, K. (1992) GABA and epilepsy: basic concepts from preclinical research. Epilepsia 33 (Suppl. 5), S3 - S12.PubMedGoogle Scholar
  36. Gallager, D. W. and Primus, R. J. (1993) Benzodiazepine tolerance and dependence:Google Scholar
  37. GABAA receptor complex locus of change. Biochem. Soc. Symp 59 135–151. Galzi, J. L. and Changeux, J. P. (1994) Neurotransmitter-gated ion channels as unconventional allosteric proteins. Curr. Opin. Struct. Biol 4 554–565.Google Scholar
  38. Gao, B. and Fritschy, J. M. (1994) Selective allocation of GABAA-receptors containing the al-subunit to neurochemically distinct subpopulations of hippocampal interneurons. Eur. J. Neurosci 6, 837–853.PubMedCrossRefGoogle Scholar
  39. Gao, B., Fritschy, J. M., Benke, D., and Möhler, H. (1993) Neuron-specific expression of GABAA-receptor subtypes: differential associations of the al-and a3-subunits with serotonergic and GABAergic neurons. Neuroscience 54, 881–892.Google Scholar
  40. Gao, B., Hornung, J. P., and Fritschy, J. M. (1995) Identification of distinct GABA,- receptor subtypes in cholinergic and parvalbumin-positive neurons of the rat and marmoset medialseptum-diagonal band complex. Neuroscience 65, 101–117.PubMedCrossRefGoogle Scholar
  41. Gunther, U., Benson, J., Benke, D., Fritschy, J. M., Reyes, G. H., Knoflach, F., Crestani, F., Aguzzi, A., Arigoni, M., Lang, Y., Bluthmann, H., Möhler, H., and Lüscher, B. (1995) Benzodiazepine-insensitive mice generated by targeted disruption of the y2-subunit gene of y-aminobutyric acid type A receptors. Proc. Natl. Acad. Sci. USA 92, 7749–7753.PubMedCrossRefGoogle Scholar
  42. Haefely, W. (1994) Allosteric modulation of the GABAA receptor channel: a mechanism for interaction with a multitude of central nervous system functions, in The Challenge of Neuropharmacology. A Tribute to the Memory of Willy Haefely ( Möhler, H. and Da Prada, M., eds.), Editiones Roche, Basel, pp. 15–40.Google Scholar
  43. Haefely, W., Martin, J. R., and Schoch, P. (1990) Novel anxiolytics that act as partial agonists at benzodiazepine receptors. Trends Pharmacol. Sci 11, 452–456.PubMedCrossRefGoogle Scholar
  44. Harris, R. A., McQuilkin, S. J., Paylor, R., Abeliovich, A., Tonegawa, S., and Wehner, J. M. (1995) Mutant mice lacking the y isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of y-aminobutyrate type A receptors. Proc. Natl. Acad. Sci. USA 92, 3658–3662.PubMedCrossRefGoogle Scholar
  45. Hayden, M. R. (1981) Huntington ‘s Chorea. Springer-Verlag, New York.CrossRefGoogle Scholar
  46. Hendry, S. H. C., Huntsman, M. M., Vinuela, A., Möhler, H., de Blas, A. L., and Jones, E. G. (1994) GABAA receptor subunit immunoreactivity in primate visual cortex: distribution in macaques and humans and regulation by visual input in adulthood. J. Neurosci 14, 2383–2401.PubMedGoogle Scholar
  47. Herb, A., Wisden, W., Luddens, H., Puia, G., Vicini, S., and Seeburg, P. H. (1992) The third y subunit of the y-aminobutyric acid type A receptor family. Proc. Natl. Acad. Sci. USA 89, 1433–1437.Google Scholar
  48. Holthoff, V. A., Koeppe, R. A., Frey, K. A., Penney, J. B., Markel, D. S., Kuhl, D. E., and Young, A. B. (1993) Positron emission tomography measures of benzodiazepine receptors in Huntington’s disease. Ann. Neurol 34, 76–81.PubMedCrossRefGoogle Scholar
  49. Hornung, J. P. and Fritschy, J. M. (1996) Developmental profile of GABAA-receptors in the marmoset monkey: expression of distinct subtypes in pre-and postnatal brain. J. Comp. Neurol 367, 413–430.Google Scholar
  50. Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983.CrossRefGoogle Scholar
  51. Huntsman, M. M., Isackson, P. J., and Jones, E. G. (1994) Lamina-specific expression and activity-dependent regulation of seven GABAA receptor subunit mRNAs in monkey visual cortex. J. Neurosci 14, 2236–2259.PubMedGoogle Scholar
  52. Im, H. K., Im, W. B., Judge, T. M., Gamill, R. B., Hamilton, B. J., Carter, D. B., and Pregenzer, J. F. (1993) Substituted pyrazinones, a new class of allosteric modulators for y-aminobutyric acid A receptors. Mol. Pharmacol 44, 468–472.PubMedGoogle Scholar
  53. Im, H. K., Im, W. B., Pregenzer, J. F., Carter, D. B., and Hamilton, B. J. (1995) U 89843 is a novel allosteric modulator of GABAA-receptors. J. Pharmacol. Exp. Ther 275, 1390–1395.PubMedGoogle Scholar
  54. Impagnatiello, F., Pesold, C., Longone, P., Caruncho, H., Fritschy, J. M., Costa, E., and Guidotti, A. (1996) Modifications of y-aminobutyric acidA receptor subunit expression in rat neocortex during tolerance to diazepam. Mol. Pharmacol 49, 822–831.PubMedGoogle Scholar
  55. Johnston, G. A. R. (1994) GABAC. receptors. Prog. Brain Res 100, 61–65.PubMedCrossRefGoogle Scholar
  56. Kamphuis, W., De Rijk, T. C., and da Silva, F. H. L. (1994) GABAA receptor ß 1–3 subunit gene expression in the hippocampus of kindled rats. Neurosci. Lett 174, 5–8.PubMedCrossRefGoogle Scholar
  57. Kamphuis, W., De Rijk, T. C., and da Silva, F. H. L. (1995) Expression of GABAA receptor subunit mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study. Mol. Brain. Res 31, 33–47.PubMedCrossRefGoogle Scholar
  58. Kang, I., Thompson, M. L., Heller, J., and Miller, L. G. (1991) Persistent elevation in GABAA receptor subunit mRNAs following social stress. Brain Res. Bull 26, 809–812.PubMedCrossRefGoogle Scholar
  59. Klein, R. L., Whiting, P. J., and Harris, R. A. (1994) Benzodiazepine treatment causes uncoupling of recombinant GABAA receptors expressed in stably transfected cells. J. Neurochem 63, 2349–2352.PubMedCrossRefGoogle Scholar
  60. Knoflach, F., Benke, D., Wang, Y., Scheurer, L., Luddens, H., Hamilton, B. J., Carter, D. B., Möhler, H., and Benson, J. A. (1996) Pharmacological modulation of the “diazepamin-sensitive” recombinant GABAA receptors a4f32y2 and a6132y2. Mol. Pharmacol (in press).Google Scholar
  61. Knoflach, F., Drescher, U., Scheurer, L., Malherbe, P., and Möhler, H. (1993) Full and partial agonism displayed by benzodiazepine receptor ligands at different recombinant GABAA receptor subtypes. J. Pharmacol. Exp. Ther 266, 385–391.PubMedGoogle Scholar
  62. Knoflach, F., Rhyner, T., Villa, M., Kellenberger, S., Drescher, U., Malherbe, P., Sigel, E., and Möhler, H. (1991) The y3-subunit of the GABAA-receptor confers sensitivity to benzodiazepine receptor ligands. FEBS Lett. 293, 191–194.PubMedCrossRefGoogle Scholar
  63. Knoll, J. H., Sinnett, D., Wagstaff, J., Glatt, K., Wilcox, A. S., Whiting, P. M., Wingrove, P., Sikela, J. M., and Lalande, M. (1993) FISH ordering of reference markers and of the gene for the a5 subunit of the y-aminobutyric acid receptor (GABAR5) within the Angelman and Prader-Willi syndrome chromosomal regions. Hum. Mol. Gen 2, 183–189.Google Scholar
  64. Kokaia, M., Pratt, G. D., Elmer, E., Bengzon, J., Fritschy, J. M., Lindvall, O., and Möhler, H. (1994) Biphasic differential changes of GABAA-receptor subunit mRNA levels in dentate gyrus granule cells following recurrent kindling induced seizures. Mol. Brain. Res 23, 323–332.Google Scholar
  65. Kusama, T., Spivak, C. E., Whiting, P., Dawson, V. L., Schaffer, J. C., and Uhl, G. R. (1993) Pharmacology of GABA p l and GABA a/ß receptors expressed in Xenopus oocytes and COS cells. Br. J. Pharmacol 109, 200–206.Google Scholar
  66. Lambert, J. J., Belelli, D., Hill Venning, C., and Peters, J. A. (1995) Neurosteroids and GABAA receptor function. Trends Pharmacol. Sci 16, 295–303.PubMedCrossRefGoogle Scholar
  67. Laurie, D. J., Seeburg, P. H., and Wisden, W (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. J. Neurosci. 12, 1063–1076.PubMedGoogle Scholar
  68. Lin, Y. F., Browning, M. D., Dudek, E. M., and Macdonald, R. L. (1994) Protein kinase C enhances recombinant bovine a1ßly2L GABAA receptor whole-cell currents expressed in L929 fibroblasts. Neuron 13, 1421–1431.PubMedCrossRefGoogle Scholar
  69. Luddens, H., Korpi, E. R., and Seeburg, P. H. (1995) GABAA/benzodiazepine receptor heterogeneity: neurophysiological implications. Neuropharmacology 34, 245–254.PubMedCrossRefGoogle Scholar
  70. Luddens, H., Pritchett, D. B., Kohler, M., Killisch, I., Keinanen, L., Monyer, H., Sprengel, R., and Seeburg, P. H. (1990) Cerebellar GABAA-receptor selective for a behavioral alcohol antagonist. Nature 346, 648–651.PubMedCrossRefGoogle Scholar
  71. Luddens, H., Seeburg, P. H., and Korpi, E. R. (1994) Impact of f:3 and y variants on ligand-binding properties of y-aminobutyric acid type A receptors. Mol. Pharmacol 45 810–814.Google Scholar
  72. Lyon, M. F., King, T. R., Gondo, Y., Gardner, J. M., Nakatsu, Y., Eicher, E. M., and Brilliant, M. H. (1992) Genetic and molecular analysis of recessive alleles at the pink-eyed dilution (p) locus of the mouse. Proc. Natl. Acad. Sci. USA 89, 6968–6972.PubMedCrossRefGoogle Scholar
  73. Macdonald, R. L. (1995) Ethanol, y-aminobutyrate type A receptors, and protein kinase C phosphorylation. Proc. Natl. Acad. Sci. USA 92, 3633–3635.PubMedCrossRefGoogle Scholar
  74. Macdonald, R. L. and Olsen, R. W. (1994) GABAA receptor channels. Annu. Rev. Neurosci 17, 569–602.PubMedCrossRefGoogle Scholar
  75. Marksitzer, R., Benke, D., Fritschy, J. M., and Möhler, H. (1993) GABAA-receptors: drug binding profile and distribution of receptors containing the a2-subunit in situ. J. Recept. Res 13 467–477.Google Scholar
  76. McDonald, J. W., Garofalo, E. A., Hood, T., Sackellares, J. C., Gilman, S., McKeever, P. E., Troncoso, J. C., and Johnston, M. V. (1991) Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy. Ann. Neurol 29, 529–541.PubMedCrossRefGoogle Scholar
  77. McKernan, R. M., Quirk, K., Prince, R., Cox, P. A., Gillard, N. P., Ragan, C. I., and Whiting, P. (1991) GABAA receptor subtypes immunopurified from rat brain with a subunit-specific antibodies have unique pharmacological properties. Neuron 7, 667–676.PubMedCrossRefGoogle Scholar
  78. McKernan, R. M. and Whiting, P. J. (1996) Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci. 19, 139–143.PubMedCrossRefGoogle Scholar
  79. Meldrum, B. (1979) Convulsant drugs, anticonvulsants and Gaba-mediated neuronal inhibition, in GABA-Neurotransmitters (Krogsgard-Larsen, P., Scheell-Kruger, J., and Kofod, H., eds.), Munksgaard, Copenhagen, pp. 390–405.Google Scholar
  80. Meldrum, B. (1995) Taking up GABA again. Nature 376, 122, 123.Google Scholar
  81. Mertens, S., Benke, D., and Möhler, H. (1993) GABAA receptor populations with novel subunit combinations and drug binding profiles identified in brain by a5- and Ssubunitspecific immunopurification. J. Biol. Chem 268, 5965–5973.PubMedGoogle Scholar
  82. Mhatre, M. and Ticku, M. K. (1994) Chronic ethanol treatment upregulates the GABAA receptor ß subunit expression. Mol. Brain. Res 23, 246–252.PubMedCrossRefGoogle Scholar
  83. Möhler, H., Fritschy, J. M., Lüscher, B., Rudolph, U., Benson, J., and Benke, D. (1995a) The GABAA-receptors: from subunits to diverse functions, in Ion Channels,vol. 4 (Narahashi, T., ed.), Plenum, New York, pp. 89–113.Google Scholar
  84. Möhler, H., Knoflach, F., Paysan, J., Motejlek, K., Benke, D., Lüscher, B., and Fritschy, J. M. (1995b) Heterogeneity of GABAA-receptors: cell-specific expression, pharmacology, and regulation. Neurochem. Res 20, 631–636.PubMedCrossRefGoogle Scholar
  85. Montpied, P., Morrow, A. L., Karanian, J. W., Ginns, E. I., Martin, B. M., and Paul, S. M. (1991) Prolonged ethanol inhalation decreases y-aminobutyric acidA receptor a subunit mRNAs in the rat cerebral cortex. Mol. Pharmacol 39, 157–163.PubMedGoogle Scholar
  86. Moss, S. J., Gorrie, G. H., Amato, A., and Smart, T. G. (1995) Modulation of GABAA receptors by tyrosine phosphorylation. Nature 377, 344–348.PubMedCrossRefGoogle Scholar
  87. Moss, S. J., Smart, T. G., Blackstone, C. D., and Huganir, R. L. (1992) Functional modulation of GABAA receptors by cAMP-dependent protein phosphorylation. Science 257, 661–665.PubMedCrossRefGoogle Scholar
  88. Nakatsu, Y., Tyndale, R. F., DeLorey, T. M., Durham-Pierre, D., Gardner, J. M., McDanel, H. J., Nguyen, Q., Wagstaff, J., Lalande, M., Sikela, J. M., Olsen, R. W., Tobin, A. J., and Brilliant, M. H. (1993) A cluster of three GABAA receptor subunit genes is deleted in a neurological mutant of the mouse p locus. Nature 364, 448–450.Google Scholar
  89. Nicholls, R. D., Gottlieb, W., Russell, L. B., Davda, M., Horsthemke, B., and Rinchik, E. M. (1993) Evaluation of potential models for imprinted and nonimprinted components of human chromosome 15q11-q13 syndromes by fine-structure homology mapping in the mouse. Proc. Natl. Acad. Sci. USA 90, 2050–2054.PubMedCrossRefGoogle Scholar
  90. Nobrega, J. N., Kish, S. J., and Burnham, W. M. (1990) Regional brain [3H]muscimol binding in kindled rat brain: a quantitative autoradiographic examination. Epilepsy Res. 6, 102–109.PubMedCrossRefGoogle Scholar
  91. Olsen, R. W. and Sapp, D. W. (1995) Neuroactive steroid modulation of GABAA receptors. Adv. Biochem. Psychopharmacol 48, 57–74.PubMedGoogle Scholar
  92. Olsen, R. W., Bureau, M., Houser, C. R., Delgado-Escueta, A. V., Richards, J. G., and Möhler, H. (1990) GABA/Benzodiazepine receptors in human focal epilepsy, in Neurotransmitters in Epilepsy, Advances in the Neurobiology of Epilepsy, vol. 1 (Avanzini, G., Engel, J., Fariello, R. G., and Heinemann, U., eds.), Demos, New York, pp. 515–527.Google Scholar
  93. Olsen, R. W., Bureau, M., Houser, C. R., Delgado-Escueta, A. V., Richards, J. G., and Möhler, H. (1992) GABA/benzodiazepine receptors in human focal epilepsy. Epilepsy Res Suppl. 8 383–391.Google Scholar
  94. Olsen, R. W., Wamsley, J. K., McCabe, R. T., Lee, R. J., and Lomax, P. (1985) Benzodiazepine/y-aminobutyric acid receptor deficit in the midbrain of the seizure-susceptible gerbils. Proc. Natl. Acad. Sci. USA 82, 6701–6705.PubMedCrossRefGoogle Scholar
  95. Paysan, J., and Fritschy, J. M. (1996) GABAA-receptor subtypes in developing brain: actors or spectators? Perspect. Dey. Neurobiol (in press).Google Scholar
  96. Pollard, S., Duggan, M. J., and Stephenson, F. A. (1991) Promiscuity of GABAA-receptor 03 subunits as demonstrated by their presence in al, a2 and a3 subunit-containing receptor subpopulations. FEBS Lett. 295, 81–83.PubMedCrossRefGoogle Scholar
  97. Porter, N. M., Twyman, R. E., Uhler, M. D., and Macdonald, R. L. (1990) Cyclic AMP-dependent protein kinase decreases GABAA receptor current in mouse spinal neurons. Neuron 5, 789–796.PubMedCrossRefGoogle Scholar
  98. Pribilla, I., Neuhaus, R., Huba, R., Hillman, M., Turner, J. D., Stephens, D. N., and Schneider, H. H. (1993) Abercanil is a full agonist at some, and a partial agonist at other recombinant GABAA receptor subtypes, in Anxiolytic ß-Carbolines ( Stephens, D. N., ed.), Springer-Verlag, Berlin, pp. 50–61.CrossRefGoogle Scholar
  99. Primus, R. J. and Gallager, D. W. (1992) GABAA receptor subunit mRNA are differentially influenced by chronic FG 7142 and diazepam exposure. Eur. J. Pharmacol 226, 21–28.PubMedCrossRefGoogle Scholar
  100. Pritchett, D. B. and Seeburg, P. H. (1990) y-Aminobutyric acidA receptor a5-subunit creates novel type II benzodiazepine receptor pharmacology. J. Neurochem 54, 1802–1804.Google Scholar
  101. Pritchett, D. B., Sontheimer, H., Shivers, B. D., Ymer, S., Kettenmann, H., Schofield, P. R., and Seeburg, P. H. (1989) Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature 338, 582–585.PubMedCrossRefGoogle Scholar
  102. Puia, G., Dudic, I., Vicini, S., and Costa, F. (1992) Molecular mechanisms of the partial allosteric modulatory effects of bretazenil at y-aminobutyric acid type A receptor. Proc. Natl. Acad. Sci. USA 89, 3620–3624.PubMedCrossRefGoogle Scholar
  103. Reis, A., Kunze, J., Ladanyi, L., Enders, H., Klein-Vogler, U., and Niemann, G. (1993) Exclusion of the GABAA-receptor (33 subunit gene as the Angelman’s syndrome gene. Lancet 341, 122–123.Google Scholar
  104. Richards, G., Schoch, P., and Haefely, W. (1991) Benzodiazepine receptors: new vistas. Semin. Neurosci 3, 191–203.CrossRefGoogle Scholar
  105. Ruano, D., Araujo, F., Machado, A., de Blas, A. L., and Vitorica, J. (1994) Molecular characterization of type I GABAA receptor complex from rat cerebral cortex and hippocampus. Mol. Brain. Res 25, 225–233.PubMedCrossRefGoogle Scholar
  106. Saitoh, S., Kubota, T., Ohta, T., Jinno, Y., Niikawa, N., Sugimoto, T., Wagstaff, J., and Lalande, M. (1992) Familial Angelman Syndrome caused by imprinted submicroscopic deletion encompassing GABAA receptor b3-subunit gene. Lancet 339, 366, 367.Google Scholar
  107. Savic, I., Roland, P., Sedvall, G., Persson, A., Pauli, S., and Widen, L. (1988) In vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancet 2, 863–866.PubMedCrossRefGoogle Scholar
  108. Saxena, N. C. and Macdonald, R. L. (1994) Assembly of GABAA receptor subunits: role of the 6 subunit. J. Neurosci 14, 7077–7086.PubMedGoogle Scholar
  109. Scharf, M. B., Mayleben, D. W., Kaffeman, M., Krall, R., and Ochs, R. (1991) Dose response effects of zolpidem in normal geriatric subjects. J. Clin. Psychiatry 52, 77–83.PubMedGoogle Scholar
  110. Schoch, P., Moreau, J. L., Martin, J. R., and Haefely, W. E. (1993) Aspects of benzodiazepine receptor structure and function with relevance to drug tolerance and dependence. Biochem. Soc. Symp 59, 121–134.PubMedGoogle Scholar
  111. Shimada, S., Cutting, G., and Uhl, G. R. (1992) y-aminobutyric acid A or C receptor? yAminobutyric acid ro 1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepineinsensitive y-aminobutyric acid responses in Xenopus oocytes. Mol. Pharmacol 41, 683–687.Google Scholar
  112. Sieghart, W. (1992) GABAA receptors: ligand-gated Cl-ion channels modulated by multiple drug binding sites. Trends Pharmacol. Sci 13, 446–450.PubMedCrossRefGoogle Scholar
  113. Sieghart, W. (1995) Structure and pharmacology of y-aminobutyric acidA receptor subtypes. Pharmacol. Rev 47, 181–234.PubMedGoogle Scholar
  114. Sigel, E. (1995) Functional modulation of ligand-gated GABAA and NMDA receptor channels by phosphorylation. J. Recept. Res 15, 325–332.Google Scholar
  115. Sinnett, D., Wagstaff, J., Glatt, K., Woolf, E., Kirkness, E. J., and Lalande, M. (1993) High-resolution mapping of the y-aminobutyric acid receptor subunit 33 and a5 gene cluster on chromosome 15g11-q13, and localization of breakpoint in two Angelman syndrome patients. Am. J. Hum. Genet 52, 1216–1229.PubMedGoogle Scholar
  116. Smith, G. B. and Olsen, R. W. (1995) Functional domains of GABAA-receptors. Trends Pharmacol. Sci 16, 162–168.PubMedCrossRefGoogle Scholar
  117. Stephenson, F. A. (1995) The GABAA receptors. Biochem. J 310, 1–9.PubMedGoogle Scholar
  118. Thompson, C. L., Bodewitz, G., Stephenson, F. A., and Turner, J. D. (1992) Mapping of GABAA receptor a5 and a6 subunit-like immunoreactivity in rat brain. Neurosci. Lett 144, 53–56.PubMedCrossRefGoogle Scholar
  119. Tietz, E. I., Huang, X., Weng, X., Rosenberg, H. C., and Chiu, T. H. (1993) Expression of a 1, a5, and y2 GABAA receptor subunit mRNAs measured in situ in rat hippocampus and cortex following chronic flurazepam administration. J. Mol. Neurosci 4, 277292.Google Scholar
  120. Titulaer, M. N. G., Kamphuis, W., Pool, C. W., van Heerikhuize, J. J., and da Silva, F. H. L. (1994) Kindling induces time-dependent and regional specific changes in the [3H]muscimol binding in the rat hippocampus: a quantitative autoradiographic study. Neuroscience 59, 817–826.PubMedCrossRefGoogle Scholar
  121. Titulaer, M. N. G., Kamphuis, W., and da Silva, F. H. L. (1995) Long-term and regional specific changes in 3H-flunitrazepam binding in kindled rat hippocampus. Neuroscience 68, 399–406.PubMedCrossRefGoogle Scholar
  122. Togel, M., Mossier, B., Fuchs, K., and Sieghart, W. (1994) y-Aminobutyric acidA receptors displaying association of y3-subunits with ß2/3 and different a-subunits exhibit unique pharmacological properties. J. Biol. Chem 269 12,993–12,998.Google Scholar
  123. Varecka, L., Wu, C. H., Rotter, A., and Frostholm, A. (1994) GABAA-benzodiazepine receptor a6 subunit mRNA in granule cells of the cerebellar cortex and cochlear nuclei: expression in developing and mutant mice. J. Comp. Neurol 339, 341–352.PubMedCrossRefGoogle Scholar
  124. Wada, T. and Fukuda, N. (1991) Pharmacologic profile of a new anxiolytic, DN-2327: effect of Ro-15 788 and interaction with diazepam in rodents. Psychopharmacology 103, 314–322.PubMedCrossRefGoogle Scholar
  125. Wafford, K. A., Burnett, D. M., Leidenheimer, N. J., Burt, D. R., Wand, J. B., Kofuji, P., Dunwiddie, T. V., Harris, R. A., and Sikela, J. M. (1991) Ethanol sensitivity of the GABAA receptor expressed in Xenopus oocytes requires 8 amino acids contained in the y2L subunit. Neuron 7, 27–33.PubMedCrossRefGoogle Scholar
  126. Wafford, K. A., Whiting, P. J., and Kemp, J. A. (1993) Differences in affinity and efficacy of benzodiazepine receptor ligands at recombinant y-aminobutyric acid receptor subtypes. Mol. Pharmacol 43, 240–244.PubMedGoogle Scholar
  127. Wee, E. L. and Zimmerman, E. F. (1983) Involvement of GABA in palate morphogenesis and its relation to diazepam teratogenesis in two mouse strains. Teratology 28, 15–22.PubMedCrossRefGoogle Scholar
  128. Whitehouse, P. J., Trifeletti, R. R., Jones, B. E., Folstein, S., Price, D. L., Snyder, S. H., and Kuhar, M. J. (1985) Neurotransmitter alterations in Huntington’s disease: autoradiographic and homogenate studies with special reference to benzodiazepine receptor complexes. Ann. Neurol 18, 202–210.Google Scholar
  129. Whiting, P., McKernan, R. M., and Iversen, L. L. (1990) Another mechanism for creating diversity in y-aminobutyrate type A receptors: RNA splicing directs expression of two forms of y2-subunit, one of which contains a protein kinase C phosphorylation site. Proc. Natl. Acad. Sci. USA 87, 9966–9970.PubMedCrossRefGoogle Scholar
  130. Wieland, H. A., Luddens, H., and Seeburg, P. H. (1992) A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J. Biol. Chem 267, 1426–1429.PubMedGoogle Scholar
  131. Wisden, W., Herb, A., Wieland, H., Keinanen, K., Luddens, H., and Seeburg, P. H. (1991) Cloning, pharmacological characteristics and expression pattern of the rat GABAA receptor a4 subunit. FEBS Lett. 289, 227–230.PubMedCrossRefGoogle Scholar
  132. Wolf, H. K., Spanle, M., Muller, M. B., Elger, C. E., Schramm, J., and Wiestler, O. D. (1994) Hippocampal loss of the GABAA receptor al subunit in patients with chronic pharmacoresistant epilepsies. Acta Neuropathol. 88, 313–319.Google Scholar
  133. Wong, G. and Skolnik, P. (1992) Ro 15–4513 binding to GABAA receptors: subunit com- position determines ligand efficacy. Pharmacol. Biochem. Behay 42, 107–110.CrossRefGoogle Scholar
  134. Wu, Y. X., Rosenberg, H. C., Chiu, T. H., and Zhao, T. J. (1994) Subunit-and brain region-specific reduction of GABAA receptor subunit mrnas during chronic treatment of rats with diazepam. J. Mol. Neurosci 5, 105–120.PubMedCrossRefGoogle Scholar
  135. Yasumatsu, H., Morimoto, Y., Yamamoto, Y., Takehara, S., Fukuda, T., Nakao, T., and Setoguchi, M. (1994) The pharmacological properties of Y-23684, a benzodiazepine receptor partial agonist. Br. J. Pharmacol 111, 1170–1178.PubMedCrossRefGoogle Scholar
  136. Ymer, S., Draguhn, A., Wisden, W., Werner, P., Keinanen, K., Schofield, P. R., Sprengel, R., Pritchett, D. B., and Seeburg, P. H. (1990) Structural and functional characterization of the yl subunit of GABAA/benzodiazepine receptors. EMBO J. 9, 3261–3267.Google Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • H. Möhler
  • D. Benke
  • J. Benson
  • B. Lüscher
  • U. Rudolph
  • J. M. Fritschy

There are no affiliations available

Personalised recommendations