The diversity of subunit composition in nAChRs:: Evolutionary origins, physiologic and pharmacologic consequences
The diversity of subunit composition in nAChRs:: Evolutionary origins, physiologic and pharmacologic consequences
复制标题
DOI：
10.1002/neu.10153
复制
发表时间：
2002-12-01
期刊：
影响因子：
--
通讯作者：
Changeux, JP
中科院分区：
文献类型：
--
作者：
Le Novère, N;Corringer, PJ;Changeux, JP
烟碱型乙酰胆碱受体由一个大的多基因家族编码的同源亚基组成。产生的受体寡聚体的广泛数量显示出不同的药理学特性。分子药理学研究的主要问题之一在于这种多样性的实际作用。通常认为，观察到的同源受体的药理学差异，例如内源性激动剂的EC50，或脱敏动力学，在体内具有某种生理相关性。在这里，我们提出了一个颇具挑战性的观点，即至少在给定的尼古丁受体亚单位亚家族中，体外观察到的药理可变性与体内受体蛋白的功能没有直接关系。在体内的反应预计不会对亲和力的轻微差异敏感，几个用一个亚基取代另一个亚基的功能例子已经被敲除的动物解开了。亚基的多样性可能是通过进化来保守的，主要是为了解释亚基分布模式在细胞和亚细胞水平上的拓扑多样性。由于近中性的遗传漂移，药理特性的数量变化在生理包络内是可以容忍的。然而，这种“无偿”的药理多样性对于药物的设计具有实际意义，它将专门针对生物体中存在的多种尼古丁受体中具有特定亚单位组成的特定受体寡聚体。(C)2002年威利期刊公司。
Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism. (C) 2002 Wiley Periodicals, Inc.