BENZODIAZEPINE-INDUCED MOTOR IMPAIRMENT LINKED TO POINT MUTATION IN CEREBELLAR GABA(A) RECEPTOR
BENZODIAZEPINE-INDUCED MOTOR IMPAIRMENT LINKED TO POINT MUTATION IN CEREBELLAR GABA(A) RECEPTOR
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DOI：
10.1038/361356a0
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发表时间：
1993-01-28
期刊：
影响因子：
64.8
通讯作者：
SEEBURG, PH
中科院分区：
文献类型：
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作者：
KORPI, ER;KLEINGOOR, C;SEEBURG, PH
选择性近亲繁殖的酒精不耐受（ANT）大鼠对苯二氮卓类激动剂（如地西泮）的姿势反射损伤非常敏感。ANT小脑通常缺乏对地西泮不敏感的苯二氮卓类药物[H-3]Ro15-4513的高亲和力结合（文献4,5），而在非选择菌株中，这种结合标志着含有α 6亚基的颗粒细胞特异性GABA(a) （γ -氨基丁酸）受体5,6。这种“野生型”小脑GABA(A)受体对地西安定不敏感的关键决定因素是位于α 6位置100的精氨酸残基，其中其他α亚基携带组氨酸8。在这里，我们报道了蚂蚁大鼠的α 6基因在野生型水平上表达，但携带一个点突变，在第100位产生精氨酸到谷氨酰胺的替代。因此，alpha6(Q100)beta2gamma2受体表现出地西泮介导的gaba激活电流增强和地西泮对[H-3]Ro15-4513的敏感结合。我们的研究结果表明，小脑运动控制可能是含有α 6亚基的GABA受体亚型的独特行为相关。
THE selectively outbred alcohol-non-tolerant (ANT) rat line1 is highly susceptible to impairment of postural reflexes by benzodiazepine agonists2 such as diazepam. ANT cerebella are generally devoid3 of diazepam-insensitive high-affinity binding of the benzodiazepine [H-3]Ro15-4513 (refs 4, 5), whereas in non-selected strains such binding marks a granule-cell-specific GABA(A) (gamma-aminobutyric acid) receptor containing the alpha6 subunit5,6. A critical determinant for diazepam insensitivity of this 'wild-type' cerebellar GABA(A) receptor is an arginine residue7 in alpha6 position 100, where other alpha subunits carry a histidine8. Here we report that the alpha6 gene of ANT rats is expressed at wild-type levels but carries a point mutation generating an arginine-to-glutamine substitution at position 100. In consequence, alpha6(Q100)beta2gamma2 receptors show diazepam-mediated potentiation of GABA-activated currents and diazepam-sensitive binding of [H-3]Ro15-4513. Our results suggest that cerebellar motor control may be a distinct behavioural correlate of the alpha6-subunit-containing GABA(A) receptor subtype.