Cerebellar GABAA receptor selective for a behavioural alcohol antagonist (original) (raw)

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.

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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
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  2. Dolan B. Pritchett
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  3. Martin Köhler
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  4. Iris Killisch
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  5. Kari Keinänen
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  6. Hannah Monyer
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  7. Rolf Sprengel
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  8. Peter H. Seeburg
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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

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