Pharmacology of the short QT syndrome N588K-hERG K+ channel mutation: differential impact on selected class I and class III antiarrhythmic drugs.

British Journal of Pharmacology
Mark J McPateHarry J Witchel

Abstract

The short QT syndrome (SQTS) is associated with cardiac arrhythmias and sudden death. The SQT1 form of SQTS results from an inactivation-attenuated, gain-of-function mutation (N588K) to the human ether-à-go-go-related gene (hERG) potassium channel. Pharmacological blockade of this mutated hERG channel may have therapeutic value. However, hERG-blocking potencies of canonical inhibitors such as E-4031 and D-sotalol are significantly reduced for N588K-hERG. Here, five hERG-blocking drugs were compared to determine their relative potencies for inhibiting N588K channels, and two other inactivation-attenuated mutant channels were tested to investigate the association between impaired inactivation and altered drug potency. Whole-cell patch clamp measurements of hERG current (I(hERG)) mediated by wild-type and mutant (N588K, S631A and N588K/S631A) channels were made at 37 degrees C CHO cells. The N588K mutation attenuated I(hERG) inhibition in the following order: E-4031>amiodarone>quinidine>propafenone>disopyramide. Comparing the three inactivation mutants, the two single mutations, although occurring in different modules of the channel, attenuated inactivation to a nearly identical degree, whereas the double mutant caused considerabl...Continue Reading

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