Subunit interaction determines IKs participation in cardiac repolarization and repolarization reserve

Background - The role of I-Ks, the slow delayed rectifier K+ current, in cardiac ventricular repolarization has been a subject of debate. Methods and Results - We develop a detailed Markov model of I-Ks and its alpha-subunit KCNQ1 and examine their kinetic properties during the cardiac ventricular action potential at different rates. We observe that interaction between KCNQ1 and KCNE1 (the beta-subunit) confers kinetic properties on I-Ks that make it suitable for participation in action potential repolarization and its adaptation to rate changes; in particular, the channel develops an available reserve of closed states near the open state that can open rapidly on demand. Conclusions - Because of its ability to form an available reserve, I-Ks can function as a repolarization reserve when I-Kr, the rapid delayed rectifier, is reduced by disease or drug and can prevent excessive action potential prolongation and development of arrhythmogenic early afterdepolarizations.