Referenced in: none

Automatically associated channels: Kv11.1

Title: 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

Journal, date & volume: Acta Pharmacol. Sin., 2004 May , 25, 554-60

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/15132818

Abstract
To determine the mechanisms of interactions between different drugs and HERG channels.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.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).The inactivation gating of HERG channels determines the blocking potency of drugs. This mechanism might be common to drugs of various classes.