IKR

IKr, the rapid component of the delayed rectifier potassium current, is a key ionic current that contributes to the repolarization phase of the cardiac action potential. In ventricular, atrial, and Purkinje cells, it flows outward during the later phases of the action potential and helps determine action potential duration and the refractory period. IKr is carried mainly by hERG (human ether-à-go-go-related gene) encoded potassium channels, which are expressed in cardiac myocytes. These channels activate quickly during depolarization but undergo rapid inactivation; during repolarization, channels recover from inactivation and produce a substantial outward current that accelerates repolarization. The resulting current shapes phase 3 repolarization and limits action potential duration. The current density and kinetics vary among species and cardiac regions.

Genetics and physiology: the IKr current is encoded by the KCNH2 gene. Loss-of-function mutations cause congenital long QT syndrome type 2, with a prolonged QT interval and risk of torsades de pointes. Regulation includes voltage dependence, temperature, and cellular signaling; IKr exhibits reverse-use dependence, being more sensitive to blockade at slower heart rates in many drugs.

Pharmacology and clinical relevance: IKr is a common target for drug-induced arrhythmias; many medications including antiarrhythmics, antibiotics, and antipsychotics can block hERG channels, increasing the QT interval. Consequently, safety testing in drug development emphasizes hERG blockade and QT monitoring. Therapeutically, proper IKr function is essential for normal cardiac repolarization, and dysregulation can predispose to ventricular and other arrhythmias. IKr interacts with other repolarizing currents, notably IKs, to determine overall action potential duration and electrical stability.