IKr: The hERG Channel

Abstract

G.-N. Tseng. IKr: The hERG Channel. Journal of Molecular and Cellular Cardiology (2001) 33, 835–849. The rapid delayed rectifier (IKr) channel is important for cardiac action potential repolarization. Suppressing IKrfunction, due to either genetic defects in its pore-forming subunit (hERG) or adverse drug effects, can lead to long-QT (LQT) syndrome that carries increased risk of life-threatening arrhythmias. The implication of IKrin cardiac arrhythmias and in anti-arrhythmic/pro-arrhythmic actions of drugs has driven intensive research interests in its structure–function relationship, the linkage between LQT-associated mutations and changes in channel function, and the mechanism of drug actions. This review will cover the following topics: (1) heterogeneous contribution of IKrto action potential repolarization in the heart, (2) structure–function relationship of IKr/hERG channels, (3) role of regulatory β subunits in IKr/hERG channel function, (4) structural basis for the unique pharmacological properties of IKr/hERG channels, and (5) IKr/hERG channel modulation by changes in cellular milieu under physiological and pathological conditions of the heart. It is anticipated that further advances in our understanding of IKr/hERG, particularly in the areas of roles of different (α and β) subunits in native IKrfunction, alterations in IKrfunction in diseased hearts, and the 3-dimensional structure of the IKr/hERG pore based on homology modeling using the KcsA model, will help us better define the role of IKrin arrhythmias and design therapeutic agents that can increase IKrand are useful for LQT syndrome.