Inactivation gating determines drug potency:a common mechanism for drug blockade of HERG channels

• 来源期刊: 中国药理学报（英文版）
• 关键词: antiarrhythmic agents potassium channels mutation channel inactivation patch-clamp techniques oocytes Xenopus
• 年，卷（期）: 2004,（5）
• 页码范围: 554-560
• 页数: 7页
• 语种: 英文

摘要

AIM: To determine the mechanisms of interactions between different drugs and HERG channels. METHODS:Various antiarrhythmic (dofetilide, quinidine, azimilide, RP58866) and non-antiarrhythmic (terfenadine, nicotine)agents were used on HERG channels expressed in Xenopus oocyte. Whole-cell voltage-clamp techniques were used. RESULTS: All drugs produced concentration-dependent block of HERG current. The inhibition was markedly facilitated with voltage protocols favoring channel inactivation (eg, less negative holding potentials). Maneuvers that weakened channel inactivation (eg, elevation of external K+), relieved HERG blockade by all drugs. Moreover,the inhibitory potency was reduced by at least 20-300 fold with varying compounds when rapid C-type inactivation was removed by a mutation located between the transmembrane domains 5 and 6 (S631A). CONCLUSION: The inactivation gating of HERG channels determines the blocking potency of drugs. This mechanism might be common to drugs of various classes.