Inactivation of HERG potassium channels: Dynamic changes in the outer pore structure

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Sudden cardiac death, due to disturbances in the normal electrical activity of the heart, is one of the leading causes of death in Australia and its incidence is increasing. Tackling the problem of cardiac arrhythmias is therefore one of the major challenges for cardiology in the 21st century. Two factors are greatly limiting progress in this area, the inability to predict who is most at risk and a paucity of treatment options. To address these problems, we need to better understand the basic mechanisms underlying arrhythmias. The rhythm of the heart beat is controlled by electrical signals mediated by the flow of ions through specialised proteins called ion channels. Of the channels that contribute to cardiac electrical activity, potassium ion channels encoded by the Human ether-a-go-go-related gene (HERG) have been of particular interest for three reasons. Firstly, mutations in HERG are the cause of one third of cases of congenital long QT syndrome, an inherited cause of sudden cardiac death. Secondly, HERG is the molecular target for the vast majority of drugs that cause drug-induced long QT syndrome, the commonest cause of drug-induced arrhythmias and cardiac death. Thirdly, HERG channels have very unusual biophysical properties, which has led to the suggestion that they may act as an endogenous anti-arrhythmic agent . Accordingly, the major objective of the proposed research program is to understand the molecular and structural basis of the unusual properties of HERG channels. We will use a combination of molecular and electrical techiques in conjunction with computer modeling to probe the micoscopic motions in the channel that underly the unusual biophyscial properties of these channels. This work will facilitate a better understanding of how clinically identified mutations in HERG contribute to the increased risk of cardiac arrhythmias. More generally, it will improve our understanding of how cardiac ion channels maintain the normal rhythm of the heart.