A nonequilibrium binary elements-based kinetic model for benzodiazepine regulation of GABAA receptors
A nonequilibrium binary elements-based kinetic model for benzodiazepine regulation of GABAA receptors
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DOI：
10.1085/jgp.201411183
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发表时间：
2014-07-01
影响因子：
3.8
通讯作者：
Pearce, Robert A.
中科院分区：
文献类型：
--
作者：
Goldschen-Ohm, Marcel P.;Haroldson, Alexander;Pearce, Robert A.
离子通道像许多其他蛋白质一样，由多个结构域组成。作用于一个结构域的刺激，如配体与其识别位点的结合，可以通过结构域间的相互作用影响另一个结构域的活性，如跨膜通道门。描述相互作用域的功能的动力学方案通常包含最少数量的状态和转变，并且不显式地模型域之间的相互作用。在这里，我们建立了GABA(A)受体的动力学模型，这是一种配体门控离子通道，受到包括苯二氮类药物在内的多种化合物的调节，苯二氮卓类药物是临床上用作镇静和抗焦虑药物的一类药物。我们的模型明确地处理了受体内不同功能结构域的动力学以及这些结构域之间的相互作用。该模型不仅描述了增强GABA(A)受体活性的苯二氮卓类药物，如安定，在存在脱敏的情况下如何影响峰电流剂量-反应关系，而且还描述了它们对不同刺激方案响应的电流激活、脱敏和失活的详细动力学的影响。最后，我们的模型解释了苯二氮卓类药物对全部或部分激动剂引起的受体电流的正向调制，并可以解决关于苯二氮卓类药物对激动剂结合的调制与通道门控的相互矛盾的观察。
Ion channels, like many other proteins, are composed of multiple structural domains. A stimulus that impinges on one domain, such as binding of a ligand to its recognition site, can influence the activity of another domain, such as a transmembrane channel gate, through interdomain interactions. Kinetic schemes that describe the function of interacting domains typically incorporate a minimal number of states and transitions, and do not explicitly model interactions between domains. Here, we develop a kinetic model of the GABA(A) receptor, a ligand-gated ion channel modulated by numerous compounds including benzodiazepines, a class of drugs used clinically as sedatives and anxiolytics. Our model explicitly treats both the kinetics of distinct functional domains within the receptor and the interactions between these domains. The model describes not only how benzodiazepines that potentiate GABA(A) receptor activity, such as diazepam, affect peak current dose-response relationships in the presence of desensitization, but also their effect on the detailed kinetics of current activation, desensitization, and deactivation in response to various stimulation protocols. Finally, our model explains positive modulation by benzodiazepines of receptor currents elicited by either full or partial agonists, and can resolve conflicting observations arguing for benzodiazepine modulation of agonist binding versus channel gating.