Lüddens H, Pritchett D B, Köhler M, Killisch I, Keinänen K, Monyer H, Sprengel R, Seeburg P H
Centre for Molecular Biology, University of Heidelberg, FRG.
Nature. 1990 Aug 16;346(6285):648-51. doi: 10.1038/346648a0.
Benzodiazepines are widely prescribed anxiolytics and anticonvulsants which bind with high affinity to sites on the GABAA receptor/Cl- channel complex and potentiate the effect of the neurotransmitter GABA (gamma-aminobutyric acid). The heterogeneity of benzodiazepine recognition sites in the central nervous system was revealed by studies showing different classes of GABAA receptor subunits (classes alpha, beta and gamma) and variant subunits in these classes, particularly in the alpha-class. Expression of recombinant subunits produces functional receptors; when certain alpha-variants are coexpressed with beta- and gamma-subunits the resulting receptors have pharmacological properties characteristic of GABAA-benzodiazepine type I or type II receptors. The alpha-variants are differentially expressed in the central nervous system and can be photoaffinity-labelled with benzodiazepines. Here we report a novel alpha-subunit (alpha 6) of cerebellar granule cells. We show that recombinant receptors composed of alpha 6, beta 2 and gamma 2 subunits bind with high affinity to the GABA agonist [3H]muscimol and the benzodiazepine [3H]Ro15-4513 but not the other benzodiazepines or beta-carboniles. The same distinctive pharmacology is observed with GABAA receptors from rat cerebellum immunoprecipitated by an antiserum specific for the alpha 6 subunit. We conclude that this alpha-subunit is part of a cerebellar receptor subtype, selective for Ro15-4513, an antagonist of alcohol-induced motor incoordination and ataxia.
苯二氮䓬类药物是广泛应用的抗焦虑药和抗惊厥药，它们以高亲和力与GABAA受体/氯离子通道复合物上的位点结合，增强神经递质γ-氨基丁酸（GABA）的作用。对中枢神经系统中苯二氮䓬类识别位点异质性的研究表明，GABAA受体亚基存在不同类别（α、β和γ类）以及这些类别中的变体亚基，特别是在α类中。重组亚基的表达产生功能性受体；当某些α变体与β和γ亚基共表达时，产生的受体具有GABAA-苯二氮䓬I型或II型受体的药理学特性。α变体在中枢神经系统中差异表达，并且可用苯二氮䓬类进行光亲和标记。在此，我们报告了一种小脑颗粒细胞的新型α亚基（α6）。我们发现，由α6、β2和γ2亚基组成的重组受体与GABA激动剂[3H]蝇蕈醇和苯二氮䓬类药物[3H]Ro15-4513具有高亲和力结合，但与其他苯二氮䓬类药物或β-羰基化合物无此结合。用针对α6亚基的抗血清免疫沉淀大鼠小脑的GABAA受体时，也观察到了相同独特的药理学特性。我们得出结论，这种α亚基是小脑受体亚型的一部分，对Ro15-4513具有选择性，Ro15-4513是一种酒精诱导的运动不协调和共济失调的拮抗剂。
