Neurochemical Research

, Volume 15, Issue 2, pp 105–112 | Cite as

From binding studies to the molecular biology of GABA receptors

  • Richard J. Knapp
  • Ewa Malatynska
  • Henry I. Yamamura
Article

Conclusions

The GABAA-complex remains enigmatic despite the substantial amount of information that has been gathered. The work of Barnard's group on the structure of the complex and the relationship of the recognition sites for GABA and benzodiazepines to its protein subunits has raised as many questions as have been answered. The existence of multiple forms of the α subunit and the ability of various combinations of the subunits to mediate GABA-gated choloride conductance suggest that there may be many forms of the GABAA-complex. Thus, the identification of previously unsuspected drug interactions, and evidence for the existence of additional endogenous ligands beside GABA (e.g. benzodiazepine-binding inhibitor (68) and certain steroids (69), all suggest that the characterization of the GABAA-complex has only begun.

Keywords

Steroid Molecular Biology Drug Interaction Recognition Site Binding Study 

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References

  1. 1.
    Schwartz, R.D. 1988. The GABAA receptor-gated ion channel: Biochemical and pharmacological studies of structure and function. Biochem. Pharmacol. 37:3369–3375.PubMedGoogle Scholar
  2. 2.
    Schofield, P.R., Darlison, M.G., Fujita, N., Burt, D.R., Stephenson, F.A., Rodriquez, H., Rhee, L.M., Ramachandran, J., Reale, V., Glencorse, T.A., Seeburg, P.H., and Barnard, E.A. 1987. Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family. Nature 328:221–227.PubMedGoogle Scholar
  3. 3.
    Levitan, E.S., Blair, L.A.C., Dionne, V.E., and Barnard, E.A. 1988. Biophysical and pharmacological properties of GABAA receptor subunit clones expressed in oocytes. Society for Neuroscience 18th annual meeting, abstract # 419.8, page 1045.Google Scholar
  4. 4.
    Blair, L.A.C., Levitan, E.S., Marshall, J., Dionne, V.E., and Barnard, E.A. 1988. Single subunits of the GABAA receptor form ion channels with properties of the native receptors. Science 242:577–579.PubMedGoogle Scholar
  5. 5.
    Roberts, E. 1986. GABA: The road to neurotransmitter status. Pages 1–39, in Olsen, R.W. and Venter, J.C. (eds.) Benzodiazepine/GABA Receptors and Chloride Channels, Alan R. Liss, New York.Google Scholar
  6. 6.
    Feltz, A., Demeneix, B., Feltz, P., Taleb, O., Trouslard, J., Bossu, J.L., Dupont, J.L. 1987. Intracellular effectors and modulators of GABAA and GABAB receptors: A commentary. Biochimie 69:395–406.PubMedGoogle Scholar
  7. 7.
    Enna, S.J. 1988. GABA-A receptors. Pages 19–106, in Squires, R.F. (ed) GABA and Benzodiazepine receptors, vol. 1, CRC Press, Boca Raton.Google Scholar
  8. 8.
    Bowery, N.G., Hill, D.R., Hudson, A.L., and Price, G.W. 1988. GABA-B receptors. Pages 107–121, in Squires, R.E. (ed) GABA and Benzodiazepine receptors, vol. I, CRC Press, Boca Raton.Google Scholar
  9. 9.
    Barker, J.L. 1988. Electrophysiological actions of GABA and diazepam in cultured CNS neurons. Pages 59–78, in Squires, R.F. (ed.) GABA and Benzodiazepine receptors, vol. I, CRC Press, Boca Raton.Google Scholar
  10. 10.
    Takeuchi, A. and Takeuchi, N. 1969. A study of the action of picrotoxin on the inhibitory neuromuscular junction of the crayfish. J. Physiol. 205:377–391.PubMedGoogle Scholar
  11. 11.
    Bowery, N.G., Collins, J.F., and Hill, R.G. 1976. Bicyclic phosphorus esters that are potent convulsants and GABA antagonists. Nature (London) 261:601–603.Google Scholar
  12. 12.
    Tallman, J.F., Paul, S.M., Skolnick, P., and Gallager, D.W. 1980. Receptors for the age of anxiety: Pharmacology of the benzodiazepines. Science 207:274–281.PubMedGoogle Scholar
  13. 13.
    Squires, R.F., and Braestrup, C. 1977. Benzodiazepine receptors in rat brain. Nature (London) 266:732–734.Google Scholar
  14. 14.
    Möhler, H. and Okada, T. 1977. Benzodiazepine receptors-demonstration in the central nervous system. Science 198:849–851.PubMedGoogle Scholar
  15. 15.
    Bosmann, H.B., Case, K.B., and Di Stefano, P. 1977. Diazepam receptor characterization: Specific binding of a benzodiazepine to macromolecules in various areas of rat brain. FEBS Lett. 82:368–371.PubMedGoogle Scholar
  16. 16.
    Speth, R.C., Wastek, G.J., Johnson, P.C. and Yamamura, H.I. 1978. Benzodiazepine binding in human brain: Characterization using3H-flunitrazepam. Life Sci. 23:859–866.Google Scholar
  17. 17.
    Möhler, H. and Okada, T. 1978. The benzodiazepine receptor in normal and pathological human brain. Br. J. Psychiatry 133:261–268.PubMedGoogle Scholar
  18. 18.
    Braestrup, C., Nielsen, M., Biggio, G. and Squires, R.F. 1979. Neuronal localization of benzodiazepine receptors in cerebellum. Neurosci. Lett. 13:219–224.PubMedGoogle Scholar
  19. 19.
    Reisine, T.D., Wastek, G.J., Speth, R.C., Bird, E.D., and Yamamura, H.I. 1979. Alterations in the benzodiazepine receptor of Huntington's diseased human brain. Brain res. 165:183–187.PubMedGoogle Scholar
  20. 20.
    Henn, F.A. and Henke, D.J. 1978. Cellular localization of [3H]diazepam receptors. Neuropharmacology 17:985–988.PubMedGoogle Scholar
  21. 21.
    Baraldi, M., Buidotti, A., Schwartz, J.P., and Costa, E. 1979. GABA receptors in clonal cell lines: A model for study of benzodiazepine action at the molecular level. Science 205:821–823.PubMedGoogle Scholar
  22. 22.
    Anholt, R.R.H. 1986. Mitochondrial benzodiazepine receptors as potential modulators of intermediary metabolism. Trends Pharmacol. Sci. 6:506–511.Google Scholar
  23. 23.
    Hirsch, J.D., Beyer, C.F., Malkowitz, L., Loullis, C.C., and Blume, A.J. 1988. Characterization of ligand binding to mitochondrial benzodiazepine receptors. Mol. Pharmacol. 35:164–172.Google Scholar
  24. 24.
    Shoemaker, H., Boles, R.G., Horst, W.D., and Yamamura, H.I. 1983. Specific high-affinity binding sites for [3H]Ro 5-4864 in rat brain and kidney. J. Pharmacol. Exp. Ther. 225:61–69.PubMedGoogle Scholar
  25. 25.
    Hirsch, J.D., Beyer, C.F., Malkowitz, L., Beer, B., and Blume, A.J. 1988. Mitochondrial benzodiazepine receptors mediate inhibition of mitochondrial respiratory control. Mol. Pharmacol. 34:157–163.Google Scholar
  26. 26.
    Squires, R.F., Benson, D., Braestrup, C., Coupet, J., Klepner, C., Myers, V., and Beer, B. 1979. Some properties of brain specific benzodiazepine receptors: New evidence for multiple receptors. Pharmacol. Biochem. Behav. 10:825–830.PubMedGoogle Scholar
  27. 27.
    Klepner, C.A., Lippa, A.S., Benson, D., Sano, M., and Beer, B. 1979. Pharmacol. Biochem. Behav. 11:457–462.PubMedGoogle Scholar
  28. 28.
    Yamamura, H.I., Mimaki, T., Yamamura, S.H., Horst, W.D., Morelli, M., Bautz, G., and O'Brien, R.A. 1982. [3H]CL 218,872. A novel triazolopyridazine which labels the benzodiazepine receptor in rat brain. Eur. J. Pharmacol. 77:351–354.PubMedGoogle Scholar
  29. 29.
    Costa, E., Guidotti, A., Mao, C.C., and Suria, A. 1975. New concepts on the mechanism of action of benzodiazepines. Life Sci. 17:167–186.PubMedGoogle Scholar
  30. 30.
    Haefely, W., Kulcsár, A., Möhler, H., Pieri, L., Polc, P., and Schaffner, R. 1975. Possible involvement of GABA in the central actions of benzodiazepines. Pages 131–151 in Costa, E. and Greengard, P. (eds) Mechanism of Action of Benzodiazepines, Adv. Biochem. Pharmacol. 14, Raven Press, New York.Google Scholar
  31. 31.
    Gallager, D.W. 1978. Benzodiazepines: Potentiation of a GABA inhibitory response in the dorsal raphe nucleus. Eur. J. Pharmacol. 49:133–143.PubMedGoogle Scholar
  32. 32.
    Tallman, J.F., Thomas, J.W., and Gallager, D.W. 1978. GABAergic modulation of benzodiazepine binding site sensitivity. Nature (London) 274:383–385.Google Scholar
  33. 33.
    Wastek, G.J., Speth, R.C., Reisine, T.D., and Yamamura, H.I. 1978. The effect of γ-aminobutyric acid on [3H]flunitrazepam binding in rat brain. Eur. J. Pharmacol. 50:445–447.PubMedGoogle Scholar
  34. 34.
    Regan, J.W., Roeske, W.R., Malick, J.B., Yamamura, S.H., and Yamamura, H.I. 1981. γ-Aminobutyric acid enhancement of CL 218,872 affinity and evidence of benzodiazepine receptor heterogeneity. Mol Pharmacol. 20:477–483.PubMedGoogle Scholar
  35. 35.
    Nielsen, M., Schou, H., and Braestrup, C. 1981. [3H]propyl β-carboline-3-carboxylate binds specifically to brain benzodiazepine receptors. J. Neurochem. 36:276–285.PubMedGoogle Scholar
  36. 36.
    Unnerstall, J.R., Kuhar, M.J., Niehoff, D.L., and Palacious, J.M. 1981. Benzodiazepine receptors are coupled to a subpopulation of γ-aminobutyric acid (GABA) receptors: Evidence from a quantitative autoradiographic study. J. Pharmacol. Exp. Ther. 218:797–804.PubMedGoogle Scholar
  37. 37.
    Stephenson, F.A. and Barnard, E.A. 1986. Purification and characterization of the brain GABA/benzodiazepine receptor. Pages 261–274 in Olsen, R.W. and Venter, J.C. (eds.) Benzodiazepine/GABA Receptors and Chloride Channels, Alan R. Liss, New York.Google Scholar
  38. 38.
    Braestrup, C., Schmiechen, R., Neef, G., Nielsen, M., and Petersen, E.N. 1982. Interaction of convulsive ligands with benzodiazepine receptors. Science 216:1241–1243.PubMedGoogle Scholar
  39. 39.
    Ehlert, F.J., Roeske, W.R., Gee, K.W., and Yamamura, H.I. 1983. An allosteric model for benzodiazepine receptor function. Biochem. Pharmacol. 32:2375–2383.PubMedGoogle Scholar
  40. 40.
    Lloyd, K.G., Morselli, P.L., and Bartholine, G. 1987. GABA and effective disorders. Med. Biol. 65:159–165.PubMedGoogle Scholar
  41. 41.
    Lloyd, K.G., Thuret, F., and Pilc, A. 1985. Upregulation of γ-aminobutyric acid (GABA) B binding sites in rat frontal cortex: A common action of repeated administration of different classes of antidepressants and electroshock. J. Pharmacol. Exp. Ther. 235:191–199.PubMedGoogle Scholar
  42. 42.
    Squires, R.F. and Saederup, E. 1988. Antidepressants and metabolites that block GABAA receptors coupled to35S-t-butylbicyclophosphorothionate binding sites in rat brain. Brain Res. 441:15–22.PubMedGoogle Scholar
  43. 43.
    Baldessarini, R.J. 1980. Drugs and the treatment of psychiatric disorders. Pages 391–447 in Gilman, A.G., Goodman, L.S., and Gilman, G. (eds.) The Pharmacological Basis of Therapeutics, MacMillan, New York.Google Scholar
  44. 44.
    Edwards, J.G. 1985. Antidepressants and seizures: Epidemiological and clinical aspects. in Trimble, M.R. (ed) The Psychopharmacology of Epilepsy. John Wiley & Sons, New York.Google Scholar
  45. 45.
    Wong, E.J.F., Leeb-Lundberg, L.M.F., Teichberg, V.I., and Olsen, R.W. 1984. γ-Aminobutyric acid activation of36Cl-flux in rat hippocampal slices and its potentiation by barbiturates. Brain Res. 303:267–275.PubMedGoogle Scholar
  46. 46.
    Thampy, K.G. and Barnes, E.M. 1984. γ-Aminobutyric acidgated chloride channels in cultured cerebral neurons. J. Biol. Chem. 259:1753–1757.PubMedGoogle Scholar
  47. 47.
    Schwartz, R.D., Skolnick, P., Hollingsworth, E.B., and Paul, S.M. 1984. Barbiturate and picrotoxin-sensitive chloride efflux in rat cerebral cortical synaptoneurosomes. FEBS Lett. 175:193–196.PubMedGoogle Scholar
  48. 48.
    Allan, A.M. and Harris, R.A. 1985. Functional coupling of γ-aminobutyric acid receptors to chloride channels in brain membranes. Science 228:1108–1110.PubMedGoogle Scholar
  49. 49.
    Hollingsworth, E.B., McNeal, E.T., Burton, J.L., Williams, R.J., Daly, J.W., and Creveling, C.R. 1985. Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: Cyclic adenosine 3′:5′-monophosphate-generating systems, receptors, and enzymes. J. Neurosci. 5:2240–2253.PubMedGoogle Scholar
  50. 50.
    Krnjevic, K. 1980. Desensitization of GABA receptors. Pages 111–120, in Costa, E., Dichiara, G., and Gessa, G.L. (eds.) GABA and Benzodiazepine Receptors, Raven Press, New York.Google Scholar
  51. 51.
    Thalmann, R.H. and Hershkowitz, N. 1985. Some factors that influence the decrement in the response to GABA during its continuous iontophoretic application to hippocampal neurons. Brain Res. 342:219–233.PubMedGoogle Scholar
  52. 52.
    Schwartz, R.D., Suzdak, P.D., and Paul, S.M. 1986. γ-Aminobutyric acid (GABA)-and barbiturate-mediated36Cl-uptake in rat brain synaptoneurosomes: Evidence for rapid desensitization of the GABA receptor-coupled chloride ion channel. Mol. Pharmacol. 30:419–426.PubMedGoogle Scholar
  53. 53.
    Cash, D.J. and Subbarao, K. 1987. Desensitization of γ-aminobutyric acid receptor from rat brain: Two distinguishable receptors on the same membrane. Biochemistry 26:7556–7562.PubMedGoogle Scholar
  54. 54.
    Cash, D.J. and Subbarao, K. 1987. Channel opening of γ-aminobutyric acid receptor from rat brain: Molecular mechanisms of the receptor responses. Biochemistry 7562–7570.Google Scholar
  55. 55.
    Cash, D.J. and Subbarao, K. 1987. Channel opening of γ-aminobutyric acid receptor from rat brain: Molecular mechanisms of the receptor responses. Biochemistry 7562–7570.Google Scholar
  56. 56.
    Guidotti, A., Gale, K., Suria, A., and Toffano, G. 1979. Biochemical evidence for two classes of GABA receptors in rat brain. Brain Res. 172:566–571.PubMedGoogle Scholar
  57. 57.
    Olsen, R.W., Wong, E.H.F., Stauber, G.B., and King, R.G. 1984. Biochemical pharmacology of the γ-aminobutyric acid receptor/ionophore protein. Federation Proc. 43:2773–2778.Google Scholar
  58. 58.
    Polc, P., Bonetti, E.P., Schaffner, R., and Haefely, W. 1982. A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquillizers, β-carbolines, and phenobarbitone. Nauyn-Schmiedebergs Arch Exp. Path. Pharmak. 321:260–264.Google Scholar
  59. 59.
    Gardner, C.R. 1988. Functional in vivo correlates of the benzodiazepine agonist-inverse agonist continuum. Prog. Neurobiol. 31:425–476.PubMedGoogle Scholar
  60. 60.
    Obata, T. and Yamamura, H.I. 1986. The effect of benzodiazepines and β-carbolines on GABA-stimulated chloride influx by membrane vesicles from the rat cerebral cortex. Biochem. Biophys. Res. Commun. 141:1–6.PubMedGoogle Scholar
  61. 61.
    Obata, T. and Yamamura, H.I. 1987. Inhibition of GABA-stimulated chloride influx by the convulsant benzodiazepine Ro 5-3663 and Ro 5-4864 into membrane vesicles from rat cerebral cortex. Eur. J. Pharmacol. 136:447–448.PubMedGoogle Scholar
  62. 62.
    Malatynska, E., Serra, M., Ikeda, M., Biggio, G., and Yamamura, H.I. 1988. Modulation of GABA-stimulated chloride intlux by β-carbolines in rat brain membrane vesicles. Brain Res. 443:395–397.PubMedGoogle Scholar
  63. 63.
    Obata, T., Morelli, M., Concas, A., Serra, M., and Yamamura, H.I. 1988. Pages 175–187, in Biggio, G. and Costa, E. (eds.) Chloride Channels and Their Modulation by Neurotransmitters and Drugs, Raven Press, New York.Google Scholar
  64. 64.
    Malatynska, E., Knapp, R.J., Ikeda, M., and Yamamura, H.I. 1988. Antidepressants and seizure-interactions at the GABA-receptor chloride-ionophore complex. Life Sci. 43:303–307.PubMedGoogle Scholar
  65. 65.
    Ikeda, M., Knapp, R., Malatynska, E., Squires, R.F., and Yamamura, H.I. (1989). Amoxapine inhibition of GABA-stimulated chloride conductance: Investigations of potential sites of activity. Life Sci. 45:1903–1910.PubMedGoogle Scholar
  66. 66.
    Lahti, R.A., Sethy, V.H., Barshn, C., and Hester, J.B. 1983. Neuropharmacology 22:1277–1282.PubMedGoogle Scholar
  67. 67.
    Obata, T., and Yamamura, H.I. 1988. Modulation of GABA-stimulated chloride influx into membrane vesicles from rat cerebral cortex by triazolobenzodiazepines. Life Sci. 42:659–665.PubMedGoogle Scholar
  68. 68.
    Guidotti, A., Forchetti, C.M., Corda, M.G., Konkel, D., Bennett, C.D., and Costa, E. 1983. Isolation, characterization, and purification to homogeneity of an endogenous polypeptide with agonist action on benzodiazepine receptors. Proc. Natl. Acad. Sci. USA 80:3531–3535.PubMedGoogle Scholar
  69. 69.
    Gee, K.W. 1988. Steroid modulation of the GABA/benzodiazepine receptor-linked chloride ionophore. Mol. Neurobiol. 2:291–317.PubMedGoogle Scholar
  70. 70.
    Enna, S.J. and Snyder, S.H. 1975. Properties of gamma-aminobutyric acid (GABA) receptor binding in rat brain synaptic membrane fractions. Brain Res. 100:81–97.PubMedGoogle Scholar
  71. 71.
    Yang, J.S.-J., and Olsen, R.W. 1987. γ-Aminobutyric acid receptor binding in fresh mouse brain membranes at 22°C: Ligandinduced changes in affinity. Mol. Pharmacol. 32:266–277.PubMedGoogle Scholar
  72. 72.
    Braestrup, C. and Squires, R. 1977. Specific benzodiazepine receptors in rat brain characterized by high affinity3H-diazepam binding. Proc. Natl. Acad. Sci. USA 74:3805–3809.PubMedGoogle Scholar
  73. 73.
    Ticku, M.K., Ban, M., and Olsen, R.W. 1978. Binding of [3H]α-dihydropicrotoxin, a γ-aminobutyric acid synaptic antagonist, to rat brain membranes. Mol. Pharmacol. 14:391–402.PubMedGoogle Scholar
  74. 74.
    Squires, R.F., Casida, J.E., Richardson, M., and Saederup, E. 1983. [35S]t-butylbicyclophosphorothionate binds with high affinity to brain-specific sites coupled to γ-aminobutyric acid-A and ion recognition sites. Mol. Pharmacol. 23:326–336.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1990

Authors and Affiliations

  • Richard J. Knapp
    • 1
  • Ewa Malatynska
    • 2
  • Henry I. Yamamura
    • 1
    • 2
  1. 1.Department of PharmacologyUniversity of Arizona College of MedicineTucson
  2. 2.Department of PsychiatryThe Ohio State University Psychopharmacology ProgramColumbus

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