Physiology and Molecular Biology of Ion Channels Contributing to Ventricular Repolarization

Ventricular action potential waveforms reflect the coordinated activity of multiple ion channels that open, close, and inactivate on different time scales (Fig. 1). The rapid upstroke of the action potential (phase 0) is caused by a large inward current through voltage-gated Na+ channels, and is followed by a transient repolarization (phase 1), reflecting Na+ channel inactivation and the activation of voltage-gated outward K+ currents (Fig. 1). This transient repolarization or "notch" influences the height and duration of the plateau phase (phase 2) of the action potential, which depends on the delicate balance of inward (Ca2+ and Na+) currents and outward (K+) currents. Although Ca2+ influx through high threshold, L-type voltage-gated Ca2+ channels is the main contributor of inward current during the plateau phase, this current declines during phase 2 as the (L-type Ca2+) channels undergo Ca2+ and voltage-dependent inactivation. The driving force for K+ efflux through the voltage-gated (and other) K+ channels, however, is high during the plateau and, as the Ca2+ channels inactivate, the outward K+ currents predominate resulting in a second, rapid phase (phase 3) of repolarization back to the resting potential (Fig. 1). The height and the duration of the action potential plateau, as well as the time- and voltage-dependent properties of the underlying voltage-gated Na+, Ca2+, and K+ currents, therefore, also influence action potential durations. As a result, modifications in the properties or the densities of any of these channels could have dramatic effects on ventricular action potential waveforms, refractory periods, and cardiac rhythms.