Keeping the Rhythm: hERG and Beyond in Cardiovascular Safety Pharmacology

Clemens Möller


Expert Rev Clin Pharmacol. 2010;3(3):321-329. 

In This Article

A Complex Concert of Ion Channels Shapes the Cardiac Action Potential

Our current understanding of the form of the human ventricular cardiac action potential, and the corresponding phases, is summarized in Figure 1.[2,3] The cardiac action potential is initiated with the rapid depolarizing upstroke mediated by sodium influx into the cell through the voltage-gated sodium ion channel NaV1.5 coded by the SCN5A gene (phase 0). Sodium ion influx is terminated by inactivation of most Na ion channels (some of which, however, remain flickering and contribute to the action potential), and is followed by Ito K+ ion flux through the KV4.3/KChIP2-coded channels, giving rise to the 'notch' seen upon termination of phase 0. It is worth noting that in many animal species, also those sometimes being used for cardiac safety testing, Ito is, in part, carried by KV4.2-coded channels. During phase 2, also referred to as the 'plateau' phase of the action potential, a balance between two ion currents is maintained. Inward movement of Ca2+ ions, mainly through L-type Ca2+ channels (CaV1.2), and outward movement of K+ ions through slow delayed rectifier K+ channels, IKs. These IKs currents have been shown to be mediated by flux of ions through KCNQ1 channels coassembled with KCNE1. During the rapid repolarization phase 3, Ca2+ channels close, while the KV7.1 ion channels are still open. The resulting net outward current causes the cell to repolarize, which, in turn, removes inactivation of the channel coded by hERG,[4] and allows the rapid delayed rectifier current IKr to flow. This current is activated rapidly in comparison with IKs, but also inactivates rapidly and only recovers from inactivation towards the end of phase 2[5] (excellent recent reviews have been published on the hERG ion channel and its kinetics[6,7]).

Figure 1.

(A) Cardiac action potential and (B) ECG trace, with the QT interval indicated.

The cell's resting membrane potential at approximately -80 to -85 mV is maintained mainly by Kir2.1 channels during phase 4. Further ion channels, such as members of the hyperpolarization activated cyclic nucleotide-gated family (HCN), enable cells in the myocardium to depolarize spontaneously and, thus, initiate the action potential, allowing cells to act as pacemakers. This mechanism, referred to as automaticity, is of major relevance in the sinoatrial node.