Analysis of facilitation of HERG current by a class III anti-arrhythmic agent

Abstract

HERG channel is blocked by many drugs, which cause life threatening cardiac arrhythmia. However, nifekalant is effective in suppressing tachyarrhythmias without induction of serious life-threatening arrhythmia. In addition to block, some drugs such as nifekalant stimulate HERG at low potentials by shifting its activation curve to hyperpolarizing direction, which is called facilitation. We investigated the mechanism of the drug-HERG interaction by electrophysiological approach. We examined its effects on HERG mutants substituted systematically to alanine in its pore region. We found that S649 is sensitive for nifekalant-induced facilitation. Thus, it supposed that binding nifekalant at closely S649 caused the channel to the facilitation. We found that nifekalant causes facilitation of HERG current by interacting with a serine residue at a top of pore cavity by modeling of homologymodeling and docking simulation. This effect of facilitation is thought one of reasons why nifekalant is effective in suppressing ventricular tachyarrhythmias. Further studies on the detailed mechanism for facilitation should be useful for the design of clinically effective Ikr blockers with reduced proarrhythmic effects. [J Physiol Sci. 2007;57 Suppl:S232]