title: Modulatory drug action in an allosteric Markov model of ion channel behaviour: biphasic effects with access-limited binding to either a stimulatory or an inhibitory site.
abstract: Concentration-dependent biphasic effects of drugs on ion channel activity have been reported in a variety of preparations, usually with stimulatory effects seen at low concentrations followed by increasingly dominant inhibition at higher levels. Such behaviour is often interpreted as evidence for the existence of separate modulatory drug binding sites. We demonstrate in this paper that it is possible for biphasic effects to be produced in an allosteric model of a ligand-activated ion channel, where diffusion-limited binding of the modulatory drug is restricted to either a stimulatory or an inhibitory site (but not both) because of steric overlap. The possibility of such an interaction mechanism should be kept in mind when interpreting experimental data if stoichiometric evidence from complementary techniques suggests that only one drug molecule is bound per receptor/ion channel complex.
authors.affiliation: Department of Mathematics and Statistics, Murdoch University, Murdoch, WA 6150, Australia. yeo@prodigal.murdoch.edu.au
authors.forename: G F
authors.initials: GF
authors.lastname: Yeo
authors.forename: B W
authors.initials: BW
authors.lastname: Madsen
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D008390:Markov Chains; D008956:Models, Chemical; D008962:Models, Theoretical; D011485:Protein Binding / Q000187:drug effects
chemical_list: D007473:Ion Channels; D008024:Ligands