Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Cerebellar GABAA receptor selective for a behavioural alcohol antagonist

Nature volume 346, pages 648–651 (1990)Cite this article

Abstract

BENZODIAZEPINES are widely prescribed anxiolytics and anti-convulsants which bind with high affinity to sites on the GABAA receptor/Cl– channel complex and potentiate the effect of the neurotransmitter GABA (γ-aminobutyric acid)1,2. The heterogeneity of benzodiazepine recognition sites in the central nervous system1,3,4 was revealed by studies showing different classes of GABAA receptor subunits (classes α, β and γ)5–7 and variant subunits in these classes, particularly in the α-class8–11. Expression of recombinant subunits produces functional receptors; when certain α-variants are coexpressed with β- and γ-subunits the resulting receptors have pharmacological properties characteristic of GABAA–benzodiazepine type I or type II receptors6,11,12. The α-variants are differentially expressed in the central nervous system13 and can be photoaffinity-labelled with benzodiazepines1,14,15. Here we report a novel α-subunit (α6) of cerebellar granule cells. We show that recombinant receptors composed of α6, β2 and γ2 subunits bind with high affinity to the GABA agonist [3H]muscimol and the benzodiazepine [3H]Rol5-4513 (refs 14,16) but not the other benzodiazepines or β-carbolines. The same distinctive pharmacology is observed with GABAA receptors from rat cerebellum immunoprecipitated by an antiserum specific for the α6 subunit. We conclude that this α-subunit is part of a cerebellar receptor subtype, selective for Rol5-4513 (ref. 17), an antagonist of alcohol-induced motor incoordination and ataxia18.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Olsen, R. W. & Venter, C. J. (eds) Benzodiazepine/GABA Receptors and Chloride Channels: Structural and Functional Properties (Liss, New York, 1986).

  2. Möhler, H. & Okada, T. Science 198, 849–851 (1977).

    Article  ADS  Google Scholar 

  3. Squires, R. F. et al. Pharmac. Biochem. Behavior 10, 825–830 (1979).

    Article  CAS  Google Scholar 

  4. Sieghart, W. & Karobath, M. Nature 286, 285–287 (1980).

    Article  ADS  CAS  Google Scholar 

  5. Schofield, P. et al. Nature 328, 221–227 (1987).

    Article  ADS  CAS  Google Scholar 

  6. Pritchett, D. B. et al. Nature 338, 582–584 (1989).

    Article  ADS  CAS  Google Scholar 

  7. Shivers, B. D. et al. Neuron 3, 327–337 (1989).

    Article  CAS  Google Scholar 

  8. Levitan, E. et al. Nature 335, 76–79 (1988).

    Article  ADS  CAS  Google Scholar 

  9. Ymer, S. et al. FEBS Lett. 258, 119–122 (1989).

    Article  CAS  Google Scholar 

  10. Krestchatisky, M. et al. Neuron 3, 745–753 (1989).

    Article  Google Scholar 

  11. Pritchett, D. B. & Seeburg, P. H. J. Neurochem. 54, 1802–1804 (1990).

    Article  CAS  Google Scholar 

  12. Pritchett D. B., Lüddens, H. & Seeburg, P. H. Science 245, 1389–1392 (1989).

    Article  ADS  CAS  Google Scholar 

  13. Wisden, W., Morris, B. J., Darlison, M. G., Hunt, S. P. & Barnard, E. A. Neuron 1, 937–947 (1988).

    Article  CAS  Google Scholar 

  14. Sieghart, W., Eichinger, A., Richards, J. G. & Mohler, H. J. Neurochem. 48, 46–52 (1987).

    Article  CAS  Google Scholar 

  15. Fuchs, K., Adamiker, D. & Sieghart, W. FEBS Lett. 261, 52–54 (1990).

    Article  CAS  Google Scholar 

  16. Malminiemi, O. & Korpi, E. R. Eur. J. Pharm. 169, 53–60 (1989).

    Article  CAS  Google Scholar 

  17. Uusi-Oukari, M. & Korpi, E. R. J. Neurochem. 54, 1980–1987 (1990).

    Article  CAS  Google Scholar 

  18. Suzdak, P. D. et al. Science 234, 1243–1247 (1986).

    Article  ADS  CAS  Google Scholar 

  19. Huganir, R. L. & Greengard, P. Trends Neurosci. 8, 472–477 (1986).

    Google Scholar 

  20. Duggan, M. J. & Stephenson, F. A. J. Neurochem. 53, 132–139 (1989).

    Article  CAS  Google Scholar 

  21. Olsen, R. W., McCabe, R. T. & Wamsley, J. K. J. clin. Neuroanat. 3, 59–76 (1990).

    CAS  Google Scholar 

  22. Squires, R. F., Saederup, E., Damgaard, I. & Schousboe, A. J. Neurochem. 54, 473–478 (1990).

    Article  CAS  Google Scholar 

  23. Lolait, S. J. et al. FEBS Lett. 246, 145–148 (1990).

    Article  Google Scholar 

  24. Palacios, J. M., Wamsley, J. K. & Kuhar, M. J. Brain Res. 222, 285–307 (1981).

    Article  CAS  Google Scholar 

  25. Unnerstall, J. R., Kuhar, M. J., Niehoff, D. L. & Palacios, J. M. J. Pharmac. exp. Ther. 218, 797–804 (1981).

    CAS  Google Scholar 

  26. McCabe, R. T. & Wamsley, J. K. Life Sci. 39, 1937–1945 (1986).

    Article  CAS  Google Scholar 

  27. Towbin, H., Staehelin, T. & Gordon, J. Proc. natn. Acad. Sci. U.S.A. 76, 4350–4355 (1979).

    Article  ADS  CAS  Google Scholar 

  28. Ewert, M. et al. J. Cell Biol. 110, 2043–2048 (1990).

    Article  CAS  Google Scholar 

  29. von Heijne, G. Nucleic Acids Res. 14, 4683–4690 (1986).

    Article  CAS  Google Scholar 

  30. Gorman, C. M., Gies, D. R. & McCray, G. DNA Prot engin. Tech. 2, 3–10 (1990).

    Google Scholar 

Download references

Author information

Author notes

  1. Dolan B. Pritchett

    Present address: University of Pennsylvania, Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, Pennsylvania, 19104, USA

  2. Peter H. Seeburg: To whom correspondence should be addressed.

Authors and Affiliations

  1. Laboratory of Molecular Neuroendocrinology, Centre for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, 6900, Heidelberg, FRG

    Hartmut Lüddens, Dolan B. Pritchett, Martin Köhler, Iris Killisch, Kari Keinänen, Hannah Monyer, Rolf Sprengel & Peter H. Seeburg

Authors
  1. Hartmut Lüddens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dolan B. Pritchett
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Köhler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Iris Killisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kari Keinänen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hannah Monyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rolf Sprengel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter H. Seeburg
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lüddens, H., Pritchett, D., Köhler, M. et al. Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature 346, 648–651 (1990). https://doi.org/10.1038/346648a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/346648a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing