Delayed‐rectifier potassium currents and the control of cardiac repolarization: Noble and Tsien 40 years after

Abstract

Following activation by depolarization, all excitable cells undergo repolarizing steps to return the transmembrane potential to the initial resting level (often called the ‘resting potential’). In comparison with other excitable cells, cardiac myocytes remain depolarized for substantially greater periods, generating the action potential ‘plateau’ (Fig. 1A). The unique cardiac action potential plateau permits sufficient transmembrane Ca2+ entry into the cell via voltage-gated Ca2+ channels to maintain the sarcoplasmic reticulum Ca2+ stores needed for effective contraction, which occurs when the sarcoplasmic reticulum releases Ca2+ in response to triggering by transmembrane Ca2+ entry initiated via cell depolarization. The plateau also keeps Na+ channels inactivated for a substantial ‘refractory period’, preventing excessively rapid beating rates during cardiac arrhythmias. Cardiac repolarization is a delicate and highly regulated process, governed by sets of ion channels, pumps and exchangers, as well as autonomic nervous system modulators (Conrath & Opthof, 2006). If the repolarization process is impaired, cardiac action potentials are prolonged (Fig. 1B). When prolongation becomes exaggerated, voltage-dependent Ca2+ currents have sufficient time to recover from the inactivation that occurs at the most depolarized levels of the action potential. The consequent reactivation of plateau Ca2+ currents causes abnormal, arrhythmia-generating ‘early afterdepolarizations’. When repolarization is excessively rapid, action potentials are abbreviated (Fig. 1C), permitting re-entrant arrhythmias (a form of ‘short-circuiting’ of cardiac electrical activity; for a detailed review see Nattel et al. 2007). Figure 1 Schematic representation of the cardiac action potential and the consequences of repolarization abnormalities