IKr:: The hERG channel

The rapid delayed rectifier (I-Kr) channel is important for cardiac action potential repolarization. Suppressing I-Kr function. 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 I-Kr in cardiac arrhythmias and in anti-arrhythmic/pro-arrhythmic actions of drugs has driven intensive research interests in its structure-Function relationship, the Linkage between LOT-associated mutations and changes in channel function. and the mechanism of drug actions. This review will cover the following topics: (1) heterogeneous contribution of I-Kr to action potential repolarization in the heart. (2) structure-function relationship of I-Kr/hERG channels. (3) role of regulatory beta subunits in I-Kr/hERG channel function. (4) structural basis for the unique pharmacological properties of I-Kr/hERG channels. and (5) I-Kr/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 I-Kr/hERG, particularly in the areas of roles of different (alpha and beta) subunits in native I-Kr function. alterations in I-Kr Function in diseased hearts, and the 3-dimensional structure of the I-Kr/hERG pore based on homology modeling using the KesA model. will help us better define the role of I-Kr in arrhythmias and design therapeutic agents that can increase I-Kr and are useful for LOT syndrome. (C) 2001 Academic Press.