Markov modeling of allosteric drug effects on ion channels, with particular reference to neuronal nicotinic acetylcholine receptors

Allosteric mechanisms have been suggested for an increasing number of ion c hannel drug interactions, but often these ideas are not examined quantitati vely through use of Markov models that would allow statistical estimation o f 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. S uch models would then provide the basis for inferential studies with experi mental data aimed at quantifying the magnitude of drug-induced changes on p articular channel parameters. It is shown that even small changes in agonis t binding affinity or channel gating are sufficient to produce biphasic mod ulatory drug effects in an allosteric model of nicotinic receptor activity, (C) 2000 Academic Press.