The N588K-HERG K + channel mutation in the ‘short QT syndrome’: Mechanism of gain-in-function determined at 37 °C

Abstract

The idiopathic short QT syndrome (SQTS) is characterised by an abnormally short QT interval on the electrocardiogram and by an increased risk of arrhythmia and sudden death. One variant of the syndrome is linked to missense mutations that lead to a single amino-acid change (N588K; asparagine to lysine) in the S5-Pore linker region of the cardiac HERG K + channel. This study was performed in order to determine how the N588K mutation alters HERG channel current ( I HERG) kinetics at mammalian physiological temperature. The whole-cell current–voltage ( I– V) relation for wild-type (WT) I HERG measured from Chinese Hamster Ovary cells was maximal at ∼0 mV and showed marked inward rectification positive to this. In contrast, N588K I HERG showed marked rectification only at +60 mV and at more positive voltages. The voltage dependence of activation of N588K-HERG did not differ significantly from that of WT-HERG. However, N588K I HERG had a significantly more positive inactivation V 0.5 (−8.14 ± 0.82 mV) than did WT I HERG (−70.05 ± 0.82 mV; P < 0.001, unpaired t test; n = 5 for each). Its P Na/ P K ratio was also greater. The instantaneous I– V relation for N588K I HERG under action potential voltage clamp peaked at ∼+40 mV, compared to ∼−37 mV for WT- I HERG. These findings underscore the importance of the S5-P linker in HERG channel function and indicate that N588K-HERG contributes increased repolarising current earlier in the ventricular action potential at physiological temperature due to a ∼+60 mV shift in voltage dependence of I HERG inactivation.