Gallager D W, Tallman J F
Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven 06437.
Neurochem Res. 1990 Feb;15(2):113-8. doi: 10.1007/BF00972200.
Molecular biological approaches to the GABAa receptor have resulted in new insights into the structure and pharmacology of this complex. It is known that the GABAa complex is a hetero-oligomer composed of multiple subunits which contain binding sites for the GABA, benzodiazepines and barbiturates. These subunits also contain regulatory sites for phosphorylation by intracellular kinases. There appear to be regional differences in the expression of the various subunits for the GABAa receptor complex. The functional significance of molecular heterogeneity is not yet known but it is expected that regional differences may result in pharmacologically diverse responses. Studies on the effects of chronic administration of diazepam have clearly delineated such regional differences. Chronic benzodiazepine administration results in the development of subsensitivity to the electrophysiological actions of GABA in the dorsal raphe, but not in GABA receptive neurons of the substantia nigra pars reticulata. Such data is consistent with regional heterogeneity in response to chronic benzodiazepine exposure. It is hoped that by understanding GABAa receptor heterogeneity, and its molecular basis, we can improve the existing receptor subtype specificity and pharmacology of the benzodiazepines.
针对GABAA受体的分子生物学方法为深入了解该复合体的结构和药理学提供了新视角。已知GABAA复合体是一种由多个亚基组成的异源寡聚体，这些亚基含有GABA、苯二氮䓬类药物和巴比妥类药物的结合位点。这些亚基还含有细胞内激酶磷酸化的调节位点。GABAA受体复合体的各种亚基的表达似乎存在区域差异。分子异质性的功能意义尚不清楚，但预计区域差异可能导致药理学上的不同反应。关于长期给予地西泮效果的研究已清楚地描绘出了这种区域差异。长期给予苯二氮䓬类药物会导致中缝背核中GABA的电生理作用出现敏感性降低，但黑质网状部的GABA受体神经元中则不会出现这种情况。这些数据与长期暴露于苯二氮䓬类药物时的区域异质性相符。希望通过了解GABAA受体异质性及其分子基础，我们能够提高苯二氮䓬类药物现有的受体亚型特异性和药理学特性。
