The GABAA Receptors: Structure and Function

  • F. Anne Stephenson


In recent years considerable attention has been given to the study of the GABAA receptors. This is because GABA is the major inhibitory neuro-transmitter in the mammalian central nervous system, where the GABA receptors are ubiquitous, playing an important role in the control of neuronal excitability. There are two pharmacological subclasses of GABA receptors. These are the GABAA receptor, a ligand-gated chloride ion channel, whose pharmacology is defined by the competitive antagonism by the plant alkaloid bicuculline; and the GABAB receptor which is bicuculline-insensitive and (-)baclofen-sensitive and the activation of which results in the production of second messengers via interaction with an as yet unknown G protein (for a review see Bowery, 1989; Stephenson and Dolphin, 1989). The GABAA receptor is the most characterized of the two receptor types. This is because it is the site of action of several groups of therapeutically important drugs, such as the benzodiazepines, the barbiturates and some steroids (reviewed in Olsen and Venter, 1986), each of which allosterically modulate GABAA receptor function at distinct binding sites within the receptor protein.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barnard, E. A., Darlison, M. G. and Seeburg, P. H. (1987). Molecular biology of the GABAA receptor; the receptor/channel superfamily. Trends Neurosci., 12, 502–509CrossRefGoogle Scholar
  2. 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 receptor. Science, N. Y., 242, 577–579CrossRefGoogle Scholar
  3. Bormann, J. and Kettenmann, H. (1988). Patch clamp study of γ-aminobutyric acid receptor Cl channels in cultured astrocytes. Proc. Natl Acad. Sci. USA, 85, 9336–9340PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bowery, N. G. (1989). GABAB receptors and their significance in mammalian pharmacology. Trends Pharmacol. Sci., 10, 401–407PubMedCrossRefGoogle Scholar
  5. Brisson, A. and Unwin, P. N. T. (1985). Quaternary structure of the acetylcholine receptor. Nature, 315, 474–477PubMedCrossRefGoogle Scholar
  6. Bureau, M. and Olsen, R. W. (1988). GABA/benzodiazepine receptor protein carries binding sites for both ligands on both of two major peptide subunits. Biochem. Biophys. Res. Commun., 153, 1006–1011PubMedCrossRefGoogle Scholar
  7. Casalotti, S. O., Stephenson, F. A. and Barnard, E. A. (1986). Separate subunits for agonist and benzodiazepine binding in the γ-aminobutryic acidA receptor oligomer. J. Biol. Chem., 261, 15013–15016PubMedGoogle Scholar
  8. Cockcroft, V. B., Osguthorpe, D., Barnard, E. A. and Lunt, G. G. (1990). Modelling of agonist binding to the ligand-gated ion channel super-family of receptors. Proteins, in press.Google Scholar
  9. Czajkowski, C, Gibbs, T. T. and Farb, D. H. (1989). Transmembrane topology of the γ-aminobutryic acidA/benzodiazepine receptors subcellular distribution and allosteric coupling determined in situ. Molec. Pharmacol., 35, 75–84Google Scholar
  10. Duggan, M. J. and Stephenson, F. A. (1989). Bovine γ-aminobutryic acidA receptor sequence-specific antibodies; identification of two epitopes which are recognised in both native and denatured γ-aminobutryic acidA receptors. J. Neurochem., 53, 132–139PubMedCrossRefGoogle Scholar
  11. Duggan, M. J. and Stephenson, F. A. (1990). Biochemical evidence for the existence of γ-aminobutyric acidA receptor iso-oligomers. J. Biol. Chem., 265, 3831–3835PubMedGoogle Scholar
  12. Dunn, S. M. J., Conti-Tronconi, B. M. and Raftery, M. A. (1983). Separate sites of low and high affinity for agonists on Torpedo californica acetylcholine receptor. Biochemistry, 22, 2512–2518PubMedCrossRefGoogle Scholar
  13. Garrett, K. M., Duman, R. S., Saito, N., Blume, A. J., Vitek, M. P. and Tallman, J. F. (1988). Isolation of a cDNA clone for the alpha subunit of the human GABA receptor. Biochem. Biophys. Res. Commun., 156, 1039–1045PubMedCrossRefGoogle Scholar
  14. Greeningloh, G., Rienitz, A., Schmitt, B., Methfessel, C, Zensen, M., Beyreuther, K., Gundelfinger, E. D. and Betz, H. (1987). The strychnine-binding subunit of the glycine receptor shows homology with nicotinic acetylcholine receptors. Nature, 328, 215–220CrossRefGoogle Scholar
  15. Gyenes, M., Farrant, M. and Farb, D. H. (1988). Run-down of 7-aminobutyric acidA receptor function during whole-cell recording; a possible role for phosphorylation. Molec. Pharmacol., 34, 719–723Google Scholar
  16. Hollmann, M., O’shea-Greenfeld, A., Rogers, S. W. and Heinemann, S. (1989). Cloning by functional expression of a member of the glutamate receptor family. Nature, 342, 643–648PubMedCrossRefGoogle Scholar
  17. 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 α subunit in rat brain GABAA receptors. Neuron, 3, 745–753PubMedCrossRefGoogle Scholar
  18. Kirkness, E. F., Bovenkirk, C. F., Ueda, T. and Turner, A. J. (1989). Phosphorylation of γ-aminobutyrate (GABA)/benzodiazepine receptors by cyclic AMP-dependent protein kinase. Biochem. J., 259, 613–616PubMedPubMedCentralCrossRefGoogle Scholar
  19. Kirkness, E. F. and Turner, A. J. (1988). Antibodies directed against a nonapeptide sequence of the γ-aminobutyrate (GABA) benzodiazepine receptor a subunit. Biochem. J., 256, 291–294PubMedPubMedCentralCrossRefGoogle Scholar
  20. Langosch, D, Thomas, L. and Betz, H. (1988). Conserved quaternary structure of ligand-gated ion channels: the postsynaptic glycine receptor is a pentamer. Proc. Natl Acad. Sci. USA, 85, 7394–7398PubMedPubMedCentralCrossRefGoogle Scholar
  21. Levitan, E. S., Schofield, P. R., Burt, D. R., Rhee, L. M., Wisden, W., Kohler, M., Rodriguez, H., Stephenson, F. A., Darlison, M. G., Barnard, E. A. and Seeburg, P. H. (1988). Structural and functional basis for GABAA receptor heterogeneity. Nature, 335, 76–79PubMedCrossRefGoogle Scholar
  22. Lolait, S. J., O’Carroll, A.-M., Kusano, K., Muller, J. M., Brownstein, M. J. and Mahan, L. C. (1989). Cloning and expression of a novel rat GABAA receptor. FEBS Lett., 246, 145–148PubMedCrossRefGoogle Scholar
  23. Mamalaki, C, Barnard, E. A. and Stephenson, F. A. (1989). Molecular size of the γ-aminobutyric acidA receptor purified from mammalian cerebral cortex. J. Neurochem., 52, 124–134PubMedCrossRefGoogle Scholar
  24. Mamalaki, C, Stephenson, F. A. and Barnard, E. A. (1987). The GABAA/benzodiazepine receptor is a heterotetramer of homologous α and β subunits. EMBO Jl, 6, 561–565Google Scholar
  25. Mohler, H., Malherbe, P. and Draghun, A. (1989). GABAA receptors expressed from rat α-and β-subunits in Xenopus oocytes are modulated by benzodiazepine receptor ligands. Soc. Neurosci. Abstr., 15, 997Google Scholar
  26. Moss, S. J., Smart, T., Porter, N. M., Naushaba, N., Devine, J., Stephenson, F. A., Mcdonald, R. L. and Barnard, E. A. (1990). Cloned GAB A receptors are maintained in a stable cell line: allosteric and channel properties. Eur. J. Pharmacol., in pressGoogle Scholar
  27. Nielsen, M. and Braestrup, C. (1980). Ethyl-β-carboline-3-carboxylate shows differential benzodiazepine receptor interactions. Nature, 286, 606–607PubMedCrossRefGoogle Scholar
  28. Numa, S. (1986). Molecular basis for the function of ionic channels. Biochem. Soc. Symp., 52, 119–143PubMedGoogle Scholar
  29. Olsen, R. W. and Venter, J. C. (Eds) (1986). Benzodiazepine/GABA Receptors and Chloride Channels: Structure and Functional Properties. Alan R. Liss, New YorkGoogle Scholar
  30. Pritchett, D. B., Luddens, H. and Seeburg, P. H. (1989a). Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science, N. Y., 245, 1389–1392CrossRefGoogle Scholar
  31. Pritchett, D. B., Luddens, H. and Seeburg, P. H. (1989b). Structural basis of type I and type II GABAA/benzodiazepine receptors. Soc. Neurosci. Abstr., 15, 641Google Scholar
  32. Pritchett, D. B., Schofield, P. R., Sontheimer, H., Ymer, S., Kettenmann, H. and Seeburg, P. H. (1988a). GABAA receptor cDNAs expressed in transfected cells and studied by path-clamp and binding assay. Soc. Neurosci. Abstr., 14, 641Google Scholar
  33. Pritchett, D. B., Sontheimer, H., Gorman, C. M., Kettenmann, H., Seeburg, P. H. and Schofield, P. R. (1988b). Transient expression shows ligand gating and allosteric potentiation of GABAA receptor subunits. Science, N.Y., 242, 1306–1308CrossRefGoogle Scholar
  34. Pritchett, D. B., Sontheimer, H., Shivers, B. D., Ymer, S., Kettenmann, H., Schofield, P. R. and Seeburg, P. H. (1989c). Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature, 338, 582–585PubMedCrossRefGoogle Scholar
  35. Richards, J. G., Schoch, P., Haring, P., Takacs, B. and Mohler, H. (1987). Resolving GABAA/benzodiazepine receptors; cellular and subcellular localisation in the CNS with monoclonal antibodies. J. Neurosci., 7, 1866–1886PubMedGoogle Scholar
  36. 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 GABAA receptor shows a ligand-gated receptor super-family. Nature, 323, 221–227CrossRefGoogle Scholar
  37. Schofield, P. R., Pritchett, D. B., Sontheimer, H., Kettenmann, H. and Seeburg, P. H. (1989). Sequence and expression of human GABAA receptor α1 and β1 subunits. FEBS Lett., 244, 361–364PubMedCrossRefGoogle Scholar
  38. Schofield, P. R., Shivers, B. D. and Seeburg, P. H. (1990). The role of receptor subtype diversity in the CNS. Trends Neurosci., 13, 8–11PubMedCrossRefGoogle Scholar
  39. Shivers, B. D., Killisch, I., Sprengel, R., Sontheimer, H., Kohler, M., Schofield, P. R. and Seeburg, P. H. (1989). Two novel GABAA receptor subunits exist in distinct neuronal populations. Neuron, 3, 327–337PubMedCrossRefGoogle Scholar
  40. Sieghart, W. (1989). Multiplicity GABAA-benzodiazepine receptors. Trends Pharmacol. Sci., 10, 407–411PubMedCrossRefGoogle Scholar
  41. Sigel, E., and Barnard, E. A. (1984). A 7-aminobutyric acid/benzodiazepine receptor complex from bovine cerebral cortex. Improved purification with preservation of regulatory sites and their interactions. J. Biol. Chem., 259, 7219–7223PubMedGoogle Scholar
  42. Sigel, E., Stephenson, F. A., Mamalaki, C. and Barnard, E. A. (1983). A γ-aminobutyric acid/benzodiazepine receptor complex of bovine cerebral cortex. J. Biol. Chem., 258, 6965–6971PubMedGoogle Scholar
  43. Stelzer, A., Kay, A. R. and Wong, R. K. S. (1988). GABAA receptor function in hippocampal cells is maintained by phosphorylation factors. Science, N.Y., 241, 339–341CrossRefGoogle Scholar
  44. Stephenson, F. A. (1988). Understanding the GABAA receptor: a chemically-gated ion channel. Biochem. J., 249, 21–32PubMedPubMedCentralCrossRefGoogle Scholar
  45. Stephenson, F. A. and Dolphin, A. C. (1989). GABA and glycine neu to transmission. Seminars Neurosci., 1, 115–123Google Scholar
  46. Stephenson, F. A., Duggan, M. J. and Casalotti, S. O. (1989). Identification of the α3 subunit in the GABAA receptor purified from bovine brain. FEBS Lett., 243, 358–362PubMedCrossRefGoogle Scholar
  47. Stephenson, F. A., Duggan, M. J. and Vollard, S. (1990). The γ2 subunit is an integral component of the γ-aminobutyricA receptor but the αl polypeptide is the principal site of the agonist benzodiazepine photoaffinity labelling reaction. J. Biol. Chem., in pressGoogle Scholar
  48. Whiting, P., Cooper, J., Conroy, W. G. and Lindstrom, J. (1989). Subunit stoichometry of neuronal nicotinic acetylcholine receptors. Soc. Neurosci. Abstr., 15, 496Google Scholar
  49. Wisden, W., McNaughton, L. A., Darlison, M. G., Hunt, S. P. and Barnard, E. A. (1989a). Differential distribution of GABAA receptor mRNAs in bovine cerebellum—localisation of α2 mRNA in Bergmann glia layer. Neurosci. Lett., 106, 7–12PubMedCrossRefGoogle Scholar
  50. Wisden, W., Morris, B. J., Darlison, M. G., Hunt, S. P. and Barnard, E. A. (1988). Distinct GABAA receptor a subunit mRNAs show differential patterns of expression in bovine brain. Neuron, 1, 937–947PubMedCrossRefGoogle Scholar
  51. Wisden, W., Morris, B. J., Darlison, M. G., Hunt, S. P. and Barnard, E. A. (1989b). Localisation of GABAA receptor α subunit mRNAs in relation to receptor subtypes. Molec. Brain Res., 5, 305–310PubMedCrossRefGoogle Scholar
  52. Ymer, S., Schofield, P. R., Draguhn, A., Werner, P., Kohler, M. and Seeburg, P. H. (1989a). GABAA receptor β subunit heterogeneity; functional expression of cloned cDNAs. EMBO Jl, 8, 1665–1670Google Scholar
  53. Ymer, S., Draguhn, A., Kohler, M., Schofield, P. R. and Seeburg, P. H. (1989b). Sequence and expression of a novel GABAA receptor a subunit. FEBS Lett., 258, 119–122PubMedCrossRefGoogle Scholar

Copyright information

© Macmillan Publishers Limited 1991

Authors and Affiliations

  • F. Anne Stephenson
    • 1
  1. 1.Department of Pharmaceutical ChemistrySchool of PharmacyLondonUK

Personalised recommendations