Madsen B W, Yeo G F
Department of Pharmacology, University of Western Australia, Nedlands, Western Australia, 6907, Australia.
Arch Biochem Biophys. 2000 Jan 15;373(2):429-34. doi: 10.1006/abbi.1999.1571.
Allosteric mechanisms have been suggested for an increasing number of ion channel drug interactions, but often these ideas are not examined quantitatively through use of Markov models that would allow statistical estimation of proposed coupling effects. In this paper we illustrate, using properties relevant to the neuronal nicotinic acetylcholine receptor, how these models can be used to provide insight into the behavior of cooperative systems. Such models would then provide the basis for inferential studies with experimental data aimed at quantifying the magnitude of drug-induced changes on particular channel parameters. It is shown that even small changes in agonist binding affinity or channel gating are sufficient to produce biphasic modulatory drug effects in an allosteric model of nicotinic receptor activity.
对于越来越多的离子通道药物相互作用，人们已经提出了变构机制，但这些观点往往没有通过马尔可夫模型进行定量研究，而马尔可夫模型可以对所提出的耦合效应进行统计估计。在本文中，我们利用与神经元烟碱型乙酰胆碱受体相关的特性，说明如何使用这些模型来深入了解协同系统的行为。这样的模型将为基于实验数据的推断性研究提供基础，旨在量化药物对特定通道参数的影响程度。结果表明，在烟碱型受体活性的变构模型中，即使激动剂结合亲和力或通道门控发生微小变化，也足以产生双相调节性药物效应。
