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 (I_Kr) and slow (I _Ks) K⁺ currents during the AP in order to provide insight into the molecular basis of their role in AP repolarization. Results show that I_Kr 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 I_Kr an effective determinant of AP repolarization. I_Ks 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, I_Ks can provide repolarizing current when other currents (e.g., I_Kr) are compromised by disease or drugs, thus preventing excessive AP prolongation and arrhythmic activity.