Modulation of HERG potassium channel function by drug action

Abstract

Repolarization of cardiomyocytes is mainly performed by the rapid component of the delayed rectifier potassium current, IKr, which is encoded by the human ether‐a‐go‐go‐related gene (HERG). Inhibition of HERG potassium currents by class III antiarrhythmic drugs causes lengthening of the cardiac action potential, which produces a beneficial antiarrhythmic effect. Conversely, excessive prolongation of the action potential by a wide variety of antiarrhythmic and non‐antiarrhythmic drugs may lead to acquired long‐QT syndrome, which is associated with a risk for ‘torsade de pointes’‐arrhythmias and sudden cardiac death. As a result, this undesirable side effect has prompted the withdrawal of several drugs from the market. Recent studies on HERG channel inhibition provide significant insights into the molecular factors that determine state‐, voltage‐, and use‐dependency of HERG current block. In addition, crucial properties of the putative drug binding site in HERG have been identified. The broad diversity in response to pharmacologic treatment among individuals is likely to depend on a combination of multiple factors from the fields of arrhythmia genetics, physiology and pharmacology. In conclusion, the increasing understanding of the molecular mechanisms that underlie HERG channel block by antiarrhythmic and non‐antiarrhythmic drugs may improve prevention and treatment of drug‐induced long‐QT syndrome.