Molecular basis of cardiac action potential repolarization.

The action potential (AP) is generated by transport of ions through transmembrane ion channels. Rate dependence of AP repolarization is a fundamental property of cardiac cells, and its modification by disease or drugs can lead to fatal arrhythmias. Using a computational biology approach, we investigated the gating kinetics of the rapid (IKr) and slow (IKs) K+ currents during the AP in order to provide insight into the molecular basis of their role in AP repolarization. Results show that IKr intensifies during the late AP plateau by progressively recovering from inactivation and generating a pronounced late peak of open-state occupancy. The delayed peak makes IKr an effective determinant of AP repolarization. IKs builds an available reserve of channels in closed states near the open state that can open rapidly to generate current during the AP repolarization phase. By doing so, IKs can provide repolarizing current when other currents (e.g., IKr) are compromised by disease or drugs, thus preventing excessive AP prolongation and arrhythmic activity.