GABAA -Benzodiazepine Receptors: Demonstration of Pharmacological Subtypes in the Brain

  • Richard W. Olsen
  • Michel Bureau
  • Shuichi Endo
  • Geoffrey Smith
  • Lynn Deng
  • Douglas Sapp
  • Allan J. Tobin
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 287)


The GABAA receptor is a ligand-gated chloride ion channel that mediates the majority of rapid-acting inhibitory synapses in the central nervous system (Olsen and Venter, 1986). The GABAA receptors are also the target of numerous clinically important depressant and excitatory drugs (Olsen, 1981; Tallman and Gallager, 1985; Biggio and Costa, 1988). The convulsant drug bicuculline acts as a competitive antagonist at the GABA recognition site, beta-carbolines block GABA function as ’ inverse agonists’ at the benzodiazepine recognition site, and picrotoxin and cage convulsants inhibit the chloride channel function at a site on the receptor complex distinct from the GABA and benzodiazepine receptor sites. Clinically important depressant benzodiazepines enhance GABA-mediated inhibition via their own binding sites on the receptor complex. Still additional sites on the receptor-ion channel complex mediate the action of barbiturates, steroid anesthetics, and possibly ethanol to enhance GABAA receptor function at the membrane level (Olsen and Venter, 1986; Biggio and Costa, 1988).


GABAA Receptor Photoaffinity Label Polypeptide Band Brain Regional Distribution Muscimol Binding 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barnard, E.A., Darlison, M.G., Fujita, N., Glencorse, T.A., Levitan, E.S., Reale, V., Schofield, P.R., Seeburg, P.H., Squire, M.D., and Stephenson, F.A., 1988, Molecular biology of the GABAA receptor, in: “Neuroreceptors and Signal Transduction”, S. Kito, T. Segawa, K. Kuriyama, M. Tohyama, and R.W. Olsen, eds., Plenum Press, New York.Google Scholar
  2. Biggio, G., and Costa, E., eds., 1988, “Chloride Channels and Their Modulation by Neurotransmitters and Drugs”, Raven Press, New York.Google Scholar
  3. Biggio, G., and Costa, E ., eds., 1990, “GABA and Benzodiazepine Receptor Subtypes: From Molecular Biology to Clinical Practice”, Raven Press, New York.Google Scholar
  4. Browning, M.D., Bureau, M., Dudek, E.M., and O1sen, R.W., 1990, Protein kinase C and cAMP-dependent protein kinase phosphorylate the β-subunit of the purified GABAA receptor. Natl. Acad. Sci. USA. 87:1315–1318.CrossRefGoogle Scholar
  5. Bureau, M., and Olsen, R.W., 1988, ϒ-Aminobutyric acid/benzodiazepine receptor protein carries binding sites for both ligands on both two major peptide subunits, Biochem. Biophys. Res. Commun., 153:1006–1011.PubMedCrossRefGoogle Scholar
  6. Bureau, M., and Olsen, R.W., 1990, Multiple distinct subunits of the ϒ-aminobutyric acid-A receptor protein show different ligand-binding affinities, Mol. Pharmacol., 37:497–502.PubMedGoogle Scholar
  7. Deng , L., Olsen, R.W., and Nielsen, M., 1988, [3H]Muscimol and [3H]flunitrazepam photoaffinity label the same molecular weight band in codfish brain GABA/BZ receptor. Abstr. Soc. Neurosci., 14:168.Google Scholar
  8. Deng, L., Ransom, R.W., and Olsen, R.W., 1986, [3H]Muscimol photolabels the ϒ-aminobutyric acid receptor binding site on a peptide subunit distinct from that labeled with benzodiazepines, Biochem. Biophys. Res. Commun., 138:1308–1314.PubMedCrossRefGoogle Scholar
  9. Duggan, M.J., and Stephenson, F.A., 1990, Biochemical evidence for the existence of ϒ-aminobutyrateA receptor iso-oligomers, J. Biol. Chem., 265:3831–3835.PubMedGoogle Scholar
  10. Fuchs, K., Mohler, H., and Sieghart, W., 1988, Various proteins from rat brain, specifically and irreversibly labeled by [3H]flunitrazepam, are distinct α-subunits of the GABA-benzodiazepine receptor complex, Neurosci. Lett., 90:314–319.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. Hebebrand, J., Friedl, W., Breidenbach, B., and Propping, P., 1987, Phylogenetic comparison of the photoaffinity-labeled benzodiazepine receptor subunits, J. Neurochem., 48:1103–1108.PubMedCrossRefGoogle Scholar
  13. Hebebrand, J., Friedl, W., Reichelt, R., Schmitz, E., Moller, P., and Propping, P., 1988, The shark GABA/BZ receptor: Further evidence for a not so late phylogenetic appearance of the benzodiazepine receptor, Brain Res., 446:251–261.PubMedCrossRefGoogle Scholar
  14. Johnston, G.A.R., 1986, Multiplicity of GABA receptors, in: “Benzodiazepine/GABA Receptors and Chloride Channels: Structural and Functional Properties”, R.W. Olsen and J.C. Venter, eds., Alan R. Liss, Inc., New York.Google Scholar
  15. Khrestchatisky, M., MacLennan, A.J., Chiang, M.-Y., Xu, W., Jackson, M.B., Brecha, N., Sternini, C., Olsen, R.W., and Tobin, A.J., 1989, A novel alpha-subunit in rat brain GABAA receptors, Neuron. 3:745–753.PubMedCrossRefGoogle Scholar
  16. King, R.G., Nielsen, M., Stauber, G.B., and Olsen, R.W., 1987, Convulsant/ barbiturate activities on the soluble GABA/benzodiazepine receptor complex, Eur. J. Biochem., 169:555–562.PubMedCrossRefGoogle Scholar
  17. Kuriyama, K., and Taguchi, J., 1988, Biochemical and functional properties of purified GABA receptor/benzodiazepine, receptor/chloride channel complex, and application of its antibody for immunohistochemical studies, in: “Neuroreceptors and Signal Transduction”, S. Kito, T. Segawa, K. Kuriyama, M. Tohyama, and R. Olsen, eds., Plenum Press, New York.Google Scholar
  18. Leeb-Lundberg, L.M.F., and Olsen, R.W., 1983, Heterogeneity of benzodiazepine receptor interactions with GABA and barbiturate receptors, Mol. Pharmacol., 23:315–325.PubMedGoogle Scholar
  19. Levitan, E.S., Schofield, P.R., Burt, D.R., Rhee, L.M., Wisden, W.,Köhler, M., Fujita, N., Rodriguez, H.F., Stephenson, F.A., Darlison, M.G., Barnard, E.A., and Seeburg, P.H., 1988, Structural and functional basis for GABAA receptor heterogeneity, Nature, 335:76–79.PubMedCrossRefGoogle Scholar
  20. Lippa, A.S., Beer, B., Sano, M.C., Vogel, R.A., and Meyerson, L.R., 1981, Differential ontogeny of type 1 and type 2 benzodiazepine receptors, Life Sci., 28:2343–2347.PubMedCrossRefGoogle Scholar
  21. Lo, M.M.S., Strittmatter, S.M., and Snyder, S.H., 1982, Physical separation and characterization of two types of benzodiazepine receptors, Proc. Natl. Acad. Sci. USA. 79:680–684.CrossRefGoogle Scholar
  22. McCabe, R.T., Wamsley, J.K., Yezuita, J.P., and O1sen, R.W., 1988, A novel GABAa antagonist [ 3H]SR 95531: Microscopic analysis of binding in the rat brain and allosteric modulation by several benzodiazepine and barbiturate receptor ligands, Synapse. 2:163–173.PubMedCrossRefGoogle Scholar
  23. Möhler, H., Battersby, M.K., and Richards, J.G., 1980, Benzodiazepine receptor protein identified and visualized in brain tissue by a photoaffinity label, Proc. Natl. Acad. Sci. USA. 77:1666–1670.PubMedCrossRefGoogle Scholar
  24. Nielsen, M., Braestrup, C., and Squires, R.F., 1978, Evidence for a late evolutionary appearance of brain specific benzodiazepine receptors: An investigation of 18 vertebrate and 5 invertebrate species, Brain Res., 141:342–346.PubMedCrossRefGoogle Scholar
  25. Olsen, R.W., 1981, GABA-benzodiazepine-barbiturate receptor interactions, J. Neurochem., 37:1–13.PubMedCrossRefGoogle Scholar
  26. Olsen, R.W., Bureau, M., Khrestchatisky, M., MacLennan, A.J., Chiang, M.-Y, Tobin, A.J., Xu, W., Jackson, M., Sternini, C., and Brecha, N., 1990b, Isolation of pharmacologically distinct GABA-benzodiazepine receptors by protein chemistry and cloning, in: “GABA and Benzodiazepine Receptor Subtypes: From Molecular Biology to Clinical Practice”, G. Biggio and E. Costa, eds., Raven Press, New York.Google Scholar
  27. Olsen, R.W., Bureau, M., Ransom, R.W., Deng, L., Dilber, A., Smith, G., Khrestchatisky, M., and Tobin, A.J., 1988, The GABA receptor-chloride ion channel protein complex, in: “Neuroreceptors and Signal Transduction”, S. Kito, T. Segawa, K. Kuriyama, M. Tohyama, and R.W. Olsen, eds., Plenum Press, New York.Google Scholar
  28. Olsen, R.W., McCabe, R.T., and Wamsley, J.K., 1990a, GABAA receptor subtypes: Autoradiographic comparison of GABA, benzodiazepines, and convulsant binding sites in the rat central nervous system, J. Chem. Neuroanat., 3:59–76.PubMedGoogle Scholar
  29. Olsen, R.W., Snowhill, E.W., and Wamsley, J.K., 1984, Autoradiographic localization of low affinity GABA receptors with [3H]bicuculline methochloride, Eur. J. Pharmacol., 99:247–248.PubMedCrossRefGoogle Scholar
  30. Olsen, R.W., and Tobin, A.J., 1990, Molecular biology of GABA. receptors, FASEB J., 4:1469–1480.PubMedGoogle Scholar
  31. Olsen, R.W., and Venter, J.C., eds., 1986, “Benzodiazepine/GABA Receptors and Chloride Channels: Structural and Functional Properties”, Receptor Biochemistry and Methodology, Volume 5, Alan R. Liss, New York.Google Scholar
  32. Pritchett, D.B., Lüddens, H., and Seeburg, P.H., 1989, Type I and type II GABAA-receptors produced in transfected cells, Science, 245:1389–1392.PubMedCrossRefGoogle Scholar
  33. Robinson, T.N., MacAllan, D., Lunt, G.G., and Battersby, M., 1986, The GABA receptor complex of insect central nervous system: Characterization of a benzodiazepine binding site. J. Neurochem., 47:1955–1962.PubMedCrossRefGoogle Scholar
  34. Sato, T.N., and Neale, J.H., 1989, Immunological identification of multiple α-like subunits of the ϒ-aminobutyric acidA receptor complex purified from neonatal rat cortex, J. Neurochem., 53:1089–1095.PubMedCrossRefGoogle Scholar
  35. Schoch, P., Richards, J.G., Haring, P., Takas, B., Stahli, C., Staehelin, T., Haefely, W., and Möhler, H., 1985, Co-localization of GABAA receptors and benzodiazepine receptors in the brain shown by monoclonal antibodies, Nature. 314:168–171.PubMedCrossRefGoogle Scholar
  36. Schofield, P.R., 1989, The GABAA receptor: Molecular biology reveals a complex picture, Trends Pharmacol. Sci., 10:476–478.PubMedCrossRefGoogle Scholar
  37. Schofield, P.R., Darlison, M.G., Fujita, N., Burt, D.R., Stephenson, F.A., Rodriguez, 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 GABA-A receptor shows a ligand-gated receptor super-family, Nature 328:221–227.PubMedCrossRefGoogle Scholar
  38. Shivers, B.D., Killisch, I., Sprengl, R., Sontheimer, H., Köhler, M., Schofield, P.R., and Seeburg, P.H., 1989, Two novel GABAA receptor subunits exist in distinct neuronal subpopulations, Neuron. 3:327–337.PubMedCrossRefGoogle Scholar
  39. Sieghart, W., and Drexler, G., 1983, Irreversible binding of [3H]flunitrazepam to different proteins in various brain regions, J. Neurochem., 41:47–55.PubMedCrossRefGoogle Scholar
  40. Sieghart, W., and Karobath, M., 1980, Molecular heterogeneity of benzodiazepine receptors, Nature. 286:285–287.PubMedCrossRefGoogle Scholar
  41. Sieghart, W., Mayer, A., and Drexler, G., 1983, Properties of [H]flunitrazepam binding to different benzodiazepine binding proteins, Eur. J. Pharmacol., 88:291–299.PubMedCrossRefGoogle Scholar
  42. Squires, R.F., and Saederup, E., 1982, ϒ-Aminobutyric acid receptors modulate cation binding sites coupled to independent benzodiazepine, picrotoxinin, and anion binding sites, Mol. Pharmacol., 22:327–334.PubMedGoogle Scholar
  43. Stauber, G.B., Ransom, R.W., Dilber, A.I., and Olsen, R.W., 1987, The ϒ-aminobutyric acid-benzodiazepine receptor protein from rat brain: Large-scale purification and preparation of antibodies, Eur. J. Biochem., 167:125–133.PubMedCrossRefGoogle Scholar
  44. Tallman, J., and Gallager, D., 1985, The GABAergic system: A locus of benzodiazepine action, Annu. Rev. Neurosci.. 8:21–44.PubMedCrossRefGoogle Scholar
  45. Turner, D.M., Ransom, R.W., Yang, J.S., and Olsen, R.W., 1989, Steroid anesthetics and naturally-occurring analogs modulate the ϒ-aminobutyric acid receptor complex at a site distinct from barbiturates, J. Pharmacol. Exp. Ther., 248:960–966.PubMedGoogle Scholar
  46. Unnerstall, J.R., Kuhar, M.J., Niehoff, D.L., and Palacios, J.M., 1981, Benzodiazepine receptors are coupled to a subpopulation of GABA receptors: Evidence from a quantitative autoradiographic study, J. Pharmacol. Exp. Ther., 218:797–804.PubMedGoogle Scholar
  47. Vitorica, J., Park, D., Chin, G., and deBlas, A.L., 1990, Characterization with antibodies of the ϒ-aminobutyric acidA benzodiazepine receptor complex during development of the rat brain, J. Neurochem., 54:187–194.PubMedCrossRefGoogle Scholar
  48. Yang, J., and Olsen, R.W., 1987, ϒ-Aminobutyric acid receptor binding in fresh mouse brain membranes at 22°C: Ligand-induced changes in affinity, Mol. Pharmacol., 32:266–277.PubMedGoogle Scholar
  49. Yezuita, J.P., McCabe, R.T., Barnett, A., Iorio, L.C., and Warnsley, J.K., 1988, Use of the selective benzodiazepine-1 (BZ-1) ligand [3H]2-oxo-quazepam (SCH 15–725) to localize BZ-1 receptors in the rat brain, Neurosci. Lett., 88:86–92.PubMedCrossRefGoogle Scholar
  50. Young, W.S. III, Niehoff, D.L., Kuhar, M.J., Beer, B., and Lippa, A.S., 1981, Multiple benzodiazepine receptor localization by light microscopic radiohistochemistry, J. Pharmacol. Exp. Ther., 216:425–430.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Richard W. Olsen
    • 1
  • Michel Bureau
    • 1
  • Shuichi Endo
    • 1
  • Geoffrey Smith
    • 1
  • Lynn Deng
    • 1
  • Douglas Sapp
    • 1
  • Allan J. Tobin
    • 2
  1. 1.Department of PharmacologyUniversity of CaliforniaLos AngelesUSA
  2. 2.Department of BiologyUniversity of CaliforniaLos AngelesUSA

Personalised recommendations