Compound-Induced Block of Ion Channel Pore Function: Inward-Rectifier Potassium Channels as a Model

Abstract

Small chemical compounds modulate ion channel functions. This is the reflection of ligand interactions with ion channels at their various sites. Many biophysical and biochemical researches have been performed on this subject and have provided important basic concepts on the structure-functional relationships of ion channels. Especially, ion channel blockers have been excellent tools for biophysical studies of ion channels and some of them are actually used for treating various diseases. The mechanisms underlying the blocking action of various chemical compounds, however, remain largely unknown at the atomic level, partly because of the promiscuous nature of the reaction. As one of the attempts to overcome the problem, we have adopted a novel approach combining molecular pharmacology and in silico analyses in the study of block of astroglial Kir4.1 channel by various antidepressants, including nortriptyline and fluoxetine. In molecular pharmacology experiments, we have demonstrated that Thr128 and Glu158 of Kir4.1 facing the central cavity play an important role in determining the sensitivities of the Kir channel to the antidepressants. On the other hand, we abstracted common sets of features from Kir4.1 channel blockers by the computer-aided technique that quantitatively correlates their chemical structures with IC 50 values for Kir4.1 channel current block. By combining these two lines of studies, we modeled the channel-drug interaction for Kir4.1-block, showing that the compound is accommodated between Thr128 and Glu158 within the central cavity of the channel. This combined approach may be useful to obtain some insights in the structure-function relationship of various ion channels and will shed light on the basic understandings of ion permeation and block.