@article{APS8141,
author = {Bao-feng YANG and Dong-hui XU and Chao-qian XU and Zhe LI and Zhi-min DU and Hui-zhen WANG and De-li DONG},
title = {Inactivation gating determines drug potency: a common mechanism for drug blockade of HERG channels},
journal = {Acta Pharmacologica Sinica},
volume = {25},
number = {5},
year = {2016},
keywords = {},
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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/8141}
}