MODULATORY DRUG-ACTION IN AN ALLOSTERIC MARKOV MODEL OF ION-CHANNEL BEHAVIOR - BIPHASIC EFFECTS WITH ACCESS-LIMITED BINDING TO EITHER A STIMULATORY OR AN INHIBITORY SITE

Concentration-dependent biphasic effects of drugs on ion channel activ ity have been reported in a variety of preparations, usually with stim ulatory effects seen at low concentrations followed by increasingly do minant inhibition at higher levels. Such behaviour is often interprete d as evidence for the existence of separate modulatory drug binding si tes. We demonstrate in this paper that it is possible for biphasic eff ects to be produced in an allosteric model of a ligand-activated ion c hannel, where diffusion-limited binding of the modulatory drug is rest ricted to either a stimulatory or an inhibitory site (but not both) be cause of steric overlap. The possibility of such an interaction mechan ism should be kept in mind when interpreting experimental data if stoi chiometric evidence from complementary techniques suggests that only o ne drug molecule is bound per receptor/ion channel complex. (C) 1998 E lsevier Science B.V. All rights reserved.