Biochemical Properties of the GABA/Barbiturate/Benzodiazepine Receptor-Chloride Ion Channel Complex

  • R. W. Olsen
  • E. H. F. Wong
  • G. B. Stauber
  • D. Murakami
  • R. G. King
  • J. B. Fischer
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 160)


The inhibitory neurotransmitter γ-aminobutyric acid (GABA) acts by increasing chloride permeability in the postsynaptic cell membrane. Chloride ion channels are regulated via GABA binding to its receptor. The cellular response to GABA has been shown to be enhanced by benzodiazepine and barbiturate drugs. This potentiation of GABA-mediated inhibition may explain much of the nervous system depressant action of these clinically important agents.


Gaba Receptor Allosteric Interaction Gaba Binding Diazepam Binding Bicuculline Methiodide 
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  1. 1.
    P. Supavilai and M. Karobath, Action of pyrazolpyridines as modulators of [3H]flunitrazepam binding to the GABA/ benzodiazepine receptor complex of the cerebellum, Eur. J. Pharmacol. 70: 183 (1981).Google Scholar
  2. 2.
    B. Beer, C. A. Klepner, A. S. Lippa, and R. F. Squires, Enhancement of [3H]diazepam binding by SQ 65396: a novel anti-anxiety agent, Pharmacol. Biochem. Behay. 9: 849 (1978).CrossRefGoogle Scholar
  3. 3.
    M. Williams and E. A. Risley, Enhancement of the binding of [3H]diazepam to rat brain membranes in vitro by SQ 20009, a novel anxiolytic, gamma-aminobutyric acid (GABA) and muscimol, Life Sci. 24: 833 (1979).CrossRefGoogle Scholar
  4. 4.
    P. Supavilai and M. Karobath, Stimulation of benzodiazepine receptor binding by SQ 20009 is chloride-dependent and picrotoxin-sensitive, Eur. J. Pharmacol. 60: 111 (1979).Google Scholar
  5. 5.
    M. K. Ticku, M. Ban, and R. W. Olsen, Binding of [3H]a-dihydropicrotoxinin, a γ-aminobutyric acid synaptic antagonist, to rat brain membranes, Mol. Pharmacol. 14: 391, (1978).Google Scholar
  6. 6.
    R. W. Olsen, Drug interactions at the GABA receptor ionophore complex, Ann. Rev. Pharmacol. Toxicol. 22: 245 (1982).CrossRefGoogle Scholar
  7. 7.
    R. W. Olsen, F. Leeb-Lundberg, and C. Napias, Picrotoxin and convulsant binding sites in mammalian brain, Brain Res. Bull. 5, Suppl. 2: 217 (1980).CrossRefGoogle Scholar
  8. 8.
    M. K. Ticku and R. W. Olsen, Cage convulsants inhibit picrotoxinin binding, Neuropharmacol. 18: 315 (1979).CrossRefGoogle Scholar
  9. 9.
    M. K. Ticku and R. W. Olsen, Interaction of barbiturates with dihydropicrotoxinin binding sites related to the GABA receptor-ionophore system, Life Sci. 22: 1643 (1978).Google Scholar
  10. 10.
    F. Leeb-Lundberg, A. Snowman, and R. W. Olsen, Perturbation of benzodiazepine receptor binding by pyrazolpyridines involves picrotoxinin/barbiturate receptor sites, J. Neurosci. 1: 471 (1981).Google Scholar
  11. 11.
    F. Leeb-Lundberg, A. Snowman, and R. W. Olsen, Barbiturate receptors are coupled to benzodiazepine receptors, Proc. Natl. Acad. Sci. USA 77: 7468 (1980).CrossRefGoogle Scholar
  12. 12.
    F. Leeb-Lundberg and R. W. Olsen, Interactions of barbiturates of various pharmacological categories with benzodiazepine receptors, Mol. Pharmacol. 21: 320 (1982).Google Scholar
  13. 13.
    F. Leeb-Lundberg and R. W. Olsen, Heterogeneity of benzodiazepine receptor interactions with GABA and barbiturate receptor sites, Mol. Pharmacol. 23: 315 (1983).Google Scholar
  14. 14.
    J. Eccles, R. A. Nicoll, T. Oshima, and F. J. Rubia, The anionic permeability of the inhibitory postsynaptic membrane of hippocampal pyramidal cells, Proc. R. Soc. Lond. B. 198: 345 (1977).CrossRefGoogle Scholar
  15. 15.
    R. A. Nicoll, J. C. Eccles, T. C. Oshima, and F. Rubia, Prolongation of hippocampal inhibitory post-synaptic potentials by barbiturates, Nature 258: 625 (1975).CrossRefGoogle Scholar
  16. 16.
    P. Placheta and M. Karobath, In vitro modulation by SQ 20009 and SQ 65396 of GABA receptor binding in rat CNS membranes, Eur. J. Pharmacol. 62:225 (1980).Google Scholar
  17. 17.
    R. W. Olsen and A. M. Snowman, Chloride-dependent enhancement by barbiturates of GABA receptor binding, J. Neurosci. 2: 1812 (1982).Google Scholar
  18. 18.
    P. Skolnick, K. C. Rice, J. L. Barker, and S. M. Paul, Interaction of barbiturates with benzodiazepine receptors in the central nervous system, Brain Res. 233: 143 (1982).Google Scholar
  19. 19.
    M. K. Ticku, Interaction of depressant, convulsant and anticonvulsant barbiturates with [3H]diazepam binding site at the benzodiazepine-GABA-receptor-ionophore complex, Biochem. Pharmacol. 30: 1573 (1981).CrossRefGoogle Scholar
  20. 20.
    T. Asano and N. Ogasawara, Chloride-dependent stimulation of GABA and benzodiazepine receptor binding by pentobarbital. Brain Res. 225: 212 (1981).Google Scholar
  21. 21.
    M. Willow and G. A. R. Johnston, Enhancement by anesthetic and convulsant barbiturates of GABA binding to rat brain synaptosomal membranes, J. Neurosci. 1: 364 (1981).Google Scholar
  22. 22.
    S. R. Whittle and A. J. Turner, Differential effects of sedative and anticonvulsant barbiturates on specific [3H]GABA binding to membrane preparations from rat brain cortex, Biochem. Pharmacol. 31: 2891 (1982).CrossRefGoogle Scholar
  23. 23.
    P. Supavilai, A. Mannonen, and M. Karobath, Modulation of GABA binding sites by CNS depressants and CNS convulsants, Neurochem. Int. 4: 259 (1982).Google Scholar
  24. 24.
    P. Supavilai, A. Mannonen, J. F. Collins, and M. Karobath, Anion-dependent modulation of [3H]muscimol binding and GABA-stimulated [3H]flunitrazepam binding by picrotoxin and related CNS convulsants, Eur. J. Pharmacol. 81: 687 (1982).Google Scholar
  25. 25.
    M. Willow and G. A. R. Johnston, Pharmacology of barbiturates: electrophysiological and neurochemical studies, Int. Rev. Neurobiol. 24: 15 (1983).CrossRefGoogle Scholar
  26. 26.
    J. L. Barker and D. A. Mathers, GABA receptors and the depressant action of pentobarbital, Trends in Neuroscience, p. 10, January (1981).Google Scholar
  27. 27.
    C. Braestrup and M. Nielsen, GABA reduces binding of 3H-methyl 8-carboline-3-carboxylate to brain benzodiazepine receptors, Nature 292: 472 (1981).CrossRefGoogle Scholar
  28. 28.
    H. Möhler and T. Okada, Properties of aminobutyric acid receptor binding with (+)[3H]bicuculline methiodide in rat cerebellum, Mol. Pharmacol. 14: 256 (1978).Google Scholar
  29. 29.
    R. W. Olsen and A. M. Snowman, [3H]Bicuculline methochloride binding to low affinity GABA receptor sites, J. Neurochem. 41: 1653 (1983).CrossRefGoogle Scholar
  30. 30.
    R. W. Olsen, E. H. F. Wong, G. B. Stauber, and R. G. King, Biochemical Pharmacology of the GABA Receptor/Ionophore Protein, Fed. Proc., in press.Google Scholar
  31. 31.
    E. H. F. Wong, A. M. Snowman, L. M. F. Leeb-Lundberg, and R. W. Olsen, Barbiturates allosterically inhibit GABA-benzodiazepine receptor antagonist binding, manuscript submitted.Google Scholar
  32. 32.
    J. F. Tallman, S. M. Paul, P. Skolnick, and D. W. Gallager, Receptors for the age of anxiety: pharmacology of the benzodiazepines, Science 207: 274 (1980).CrossRefGoogle Scholar
  33. 33.
    F. J. Ehlert, W. R. Roeske, K. W. Gee, and H. I. Yamamura, An allosteric model for benzodiazepine receptor function, Biochem. Pharmacol. 32: 2375 (1983).CrossRefGoogle Scholar
  34. 34.
    M. Karobath, P. Placheta, M. Lippitsch, and P. KrogsgaardLarsen, Is stimulation of benzodiazepine receptor binding mediated by a novel GABA receptor? Nature 278: 748 (1979).CrossRefGoogle Scholar
  35. 35.
    C. Braestrup, M. Nielsen, P. Krogsgaard-Larsen, and E. Falch, Partial agonists for brain GABA/benzodiazepine receptor complex, Nature 280: 331 (1979).CrossRefGoogle Scholar
  36. 36.
    M. Gavish and S. H. Snyder, y-Aminobutyric acid and benzodiazepine receptors: copurification and characterization, Proc. Natl. Acad. Sci. USA 78: 1939 (1981).CrossRefGoogle Scholar
  37. 37.
    R. F35Squires, J. E. Casida, M. Richardson, and E. Saederup, [ S]t-Butylbicyclophosphorothionate binds with high affinity to brain-specific sites coupled to y-aminobutyric acid-A and ion recognition sites, Mol. Pharmacol. 23: 326 (1983).Google Scholar
  38. 38.
    R. G. King and R. W. Olsen, Solubilization of cage convulsant/ picrotoxin/barbiturate receptors, Trans. Am. Soc. Neurochem. (1984).Google Scholar
  39. 39.
    M. K. Ticku and R. W. Olsen, y-Aminobutyric acid stimulated chloride permeability in crayfish muscle, Biochim. Biophys. Act a 464: 519 (1977).CrossRefGoogle Scholar
  40. 40.
    A. Luini, O. Goldberg, and V. I. Teichberg, Distinct pharmacological properties of excitatory amino acid receptors in the rat striatum: study by Na efflux assay, Proc. Natl. Acad. Sci. USA 78: 3250 (1981).CrossRefGoogle Scholar
  41. 41.
    E. H. F. Wong, L. M. F. Leeb-Lundberg, V. I. Teichqrg, and R. W. Olsen, y-Aminobutyric acid activation of Cl flux in rat hippocampal slices and its potentiation by barbiturates, Brain Res., in press (1984).Google Scholar
  42. 42.
    D. V. Greenlee and R. W. Olsen, Solubilization of gammaaminobutyric acid receptor protein from mammalian brain, Biochem. Biophys. Res. Comm. 88: 380 (1979).Google Scholar
  43. 43.
    F. A. Stephenson, A. E. Watkins, and R. W. Olsen, Physicochemical characterization of detergent-solubilized y-aminobutyric acid and benzodiazepine receptor proteins from bovine brain, Eur. J. Biochem. 123: 291 (1982).Google Scholar
  44. 44.
    T. Asano, Y. Yamada, and N. Ogasawara, Characterization of the solubilized GABA and benzodiazepine receptors from various regions of bovine brain, J. Neurochem. 40: 209 (1983).CrossRefGoogle Scholar
  45. 45.
    L. -R. Chang and E. A. Barnard, The benzodiazepine/GABA receptor complex: molecular size in brain synaptic membranes and in solution, J. Neurochem. 39: 1507 (1982).CrossRefGoogle Scholar
  46. 46.
    F. A. Stephenson and R. W. Olsen, Solubilization by CHAPS detergent of barbiturate-enhanced benzodiazepine-GABA receptor complex, J. Neurochem. 39: 1579 (1982).CrossRefGoogle Scholar
  47. 47.
    C. Martini, A. Lucacchini, G. Ronca, S. Hrelia, and C. A. Rossi, Isolation of putative benzodiazepine receptors from rat brain membranes by affinity chromatography, J. Neurochem. 38: 15 (1982).CrossRefGoogle Scholar
  48. 48.
    E. Sigel, C. Mamalaki, and E. A. Barnard, Isolation of a GABA receptor from bovine brain using a benzodiazepine affinity column, FEBS Lett. 147: 45 (1982).CrossRefGoogle Scholar
  49. 49.
    E. A. Barnard, F. A. Stephenson, E. Sigel, C. Mamalaki, G. Bilbe, A. Constanti, T.G. Smart, and D. A. Brown, Structure and properties of the brain GABA/benzodiazepine receptor complex, in: “Neurotransmitter Receptors: Mechanisms of Action and Regulation,” S. Kito, T. Segawa, K. Kuriyama, H. I. Yamamura, and R. W. Olsen, eds., Plenum, New York (1984).Google Scholar
  50. 50.
    K. Kuriyama and J. Taguchi, Purification of y-aminobutyric acid (GABA) and benzodiazepine receptors from rat brain using benzodiazepine-affinity column chromatography, in: “Neurotransmitter Receptors: Mechanisms of Action and Regulation,” S. Kito, T. Segawa, K. Kuriyama, H. I. Yamamura, and R. W. Olsen, eds., Plenum, New York (1984).Google Scholar
  51. 51.
    R. W. Olsen, Biochemical properties of GABA receptors, in: “The GABA Receptors,” S. J. Enna, ed., Humana Press, Clifton, New Jersey, p. 63 (1983).Google Scholar
  52. 52.
    R. W. Olsen, E. H. F. Wong, G. Stauber, D. Murakami, and J. Sussman, Progress in purification of the benzodiazepine/ GABA receptor protein, Trans. Am. Soc. Neurochem. 14: 194 (1983).Google Scholar
  53. 53.
    H. Möhler, M. K. Battersby, and J. G. Richards, Benzodiazepine receptor protein identified and visualized in brain tissue by a photoaffinity label, Proc. Natl. Acad. Sci. USA 77: 1666 (1980).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • R. W. Olsen
    • 1
    • 2
  • E. H. F. Wong
    • 1
    • 2
  • G. B. Stauber
    • 1
    • 2
  • D. Murakami
    • 1
    • 2
  • R. G. King
    • 1
    • 2
  • J. B. Fischer
    • 1
    • 2
  1. 1.Department of Biochemistry and Division of Biomedical SciencesUniversity of CaliforniaRiversideUSA
  2. 2.Department of PharmacologyUCLA School of MedicineLos AngelesUSA

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