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 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.