Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: M J McPate, R S Duncan, J C Hancox, H J Witchel

Journal, date & volume: Br. J. Pharmacol., 2008 Nov , 155, 957-66

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18724381

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 considerably greater attenuation, permitting the titration of inactivation. Attenuation of channel inhibition was similar between the single mutants for each drug, and was significantly greater with the double mutant.The degree of drug inhibition of hERG channels may vary based on the level of channel inactivation. Drugs previously identified as useful for treating SQT1 have the least dependence on hERG inactivation. In addition, our findings indicate that amiodarone may warrant further investigation as a potential treatment for SQT1.