Abstract
Short QT Syndrome (SQTS) is a potentially fatal cardiac arrhythmia, characterized by a reduced QT interval in the electrocardiogram. A gain-of-function mutation, V307L, observed in the voltage-gated potassium channel KCNQ1 gene in a SQTS patient has implicated this disease as a cardiac channelopathy. In the heart, KCNQ1 (Q1) subunits assemble with accessory subunits, KCNE1 (E1), to produce the IKs channel, which passes slow outwardly rectifying potassium current that contributes to the cardiac action potential repolarization. To understand the effect of the V307L mutation on the biophysical properties of IKs and Q1 channels, we used whole-cell patch clamp to investigate the channel gating and total internal reflection fluorescence (TIRF) microscopy to visualize the channel expression at the membrane. Electrophysiological studies indicated that the V307L mutation makes the transition from closed to open state more favorable for IKs channels, but not for Q1 channels, by shifting the half-maximal activation voltage and accelerating the activation kinetics. TIRF microscopy illustrated that the V307L mutation decreased the IKs (but not Q1) channel density. In conclusion, we propose two testable mechanisms for E1-dependent gain-of-function phenotype associated with the V307L mutation. The V307L mutation in the pore of Q1 may introduce a partially open state or decrease the energetic barrier to the voltage sensing domain movement upon depolarization of the membrane. These models illustrate how the V307L mutation may result in increased K+ efflux associated with expedited cardiac action potential repolarization and highlight the significance of the 307 site in IKs and Q1 gating.