Abstract 639: Destabilization Of The Open State Of I Ks Potassium Channels By A KCNQ1 V205M Missense Mutation Causes An Inherited Form Of LQTS In A Canadian Aboriginal Community

Abstract

Hereditary long QT syndrome (LQTS) is a genetic disease characterized by a prolonged QT interval in the electrocardiogram and an increased likelihood of serious ventricular arrhythmias. We have determined that LQTS is disproportionately prevalent in a Northern British Columbia aboriginal community. Genetic screening of affected individuals revealed a novel missense mutation (V205M) in the S3 transmembrane helix of KCNQ1, the pore forming domain of the I K s channel complex. Co-expression of V205M KCNQ1 in mammalian cells with the accessory subunit KCNE1 recapitulated I Ks , with similar surface expression to wild type (Wt) channels, but with a 33.7 mV depolarizing shift in the V 1/2 of activation. This was accompanied by a slowing of channel activation (294 ± 85 ms, n=5; and 878 ± 124 ms, n=4; for Wt and V205M channels, respectively, at +70 mV), and an acceleration of deactivation (53 ± 3.6 ms, n=5; and 14 ± 3.5, n=4; for Wt and V205M channels, at −100 mV), determined at 35°C. The heterozygous state of the channel complex was simulated by co-expressing Wt and V205M channel subunits, and this resulted in phenotypic I Ks currents with properties intermediate between Wt and V205M homomultimeric channels. Using a ventricular action potential voltage clamp protocol applied at 3 Hz, Wt channels, but not V205M channels, accumulated in the open state, which resulted in large outward I Ks currents only for Wt channels. The outward ionic charge through heteromultimeric channels during the action potential clamp was reduced by more than 75% compared to Wt channels, suggesting a functional dominant negative effect of the V205M mutation at high heart rates. The changes in I Ks kinetics produced by the V205M mutation are expected to decrease current and reduce the repolarization reserve during the cardiac ventricular action potential, with a likely increased susceptibility to the initiation of arrhythmias, especially during periods of high sympathetic drive.