Original Article

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

Authors: Bao-feng YANG, Dong-hui XU, Chao-qian XU, Zhe LI, Zhi-min DU, Hui-zhen WANG, De-li DONG

Abstract

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.
Keywords:

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