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

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 (IHERG) kinetics at mammalian physiological temperature. The whole-cell current-voltage (I-V) relation for wild-type (WT) IHERG measured from Chinese Hamster Ovary cells was maximal at ∼0 mV and showed marked inward rectification positive to this. In contrast, N588K IHERG 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 IHERG had a significantly more positive inactivation V0.5 (−8.14 ± 0.82 mV) than did WT IHERG (−70.05 ± 0.82 mV; P < 0.001, unpaired t test; n = 5 for each). Its PNa/PK ratio was also greater. The instantaneous I-V relation for N588K IHERG under action potential voltage clamp peaked at ∼+40 mV, compared to ∼−37 mV for WT-IHERG. 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 IHERG inactivation.