Long QT Syndrome-associated Mutations in the Voltage Sensor of I_Ks Channels

The plateau phase of the ventricular action potential is the result of balanced Ca2+ influx and K+ efflux. The action potential is finally terminated by repolarising K+ currents. Under beta-adrenergic stimulation the slowly activating component of the human cardiac delayed rectifier K+ current I(Ks) provides the major repolarising component. I(Ks) channels are heteromeric channels composed of KCNQ1 and KCNE1. Mutations in the voltage sensor S4 of KCNQ1 are associated with long-QT syndrome 1 (LQTS1). Here, we study the effects of the mutations S225L, I235N and L239P located in S4. The respective channels were expressed in Xenopus oocytes and analyzed by dual electrode voltage clamp. As a result all mutants shifted the voltage dependence of activation to the right and reduced the voltage dependence of deactivation kinetics. The activation kinetics were differently affected in homomeric mutant channels compared to wild type KCNQ1. All three mutations reduced KCNQ1/KCNE1 channel currents in a dominant-negative manner when the mutants were coexpressed with wt subunits suggesting reduced I(Ks) as the molecular basis of LQT1.