CEREBELLAR GABA-A RECEPTOR SELECTIVE FOR A BEHAVIORAL ALCOHOL ANTAGONIST

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. © 1990 Nature Publishing Group.