Grant: Project Grant

During the human heartbeat cycle, the cells in the heart go from rest to fully active as the heart contracts and pumps blood, and back to rest again as the heart muscle relaxes. All this happens over a time scale of about one second. Underlying this pumping action of the heart is the electrical activity within the cells, coordinated by small proteins called ion channels. When this process goes wrong, serious arrhythmias (irregular and fast heartbeats) and even sudden death may result. Antiarrhythmic compounds can be used to control these dangerous heart rhythms and restore normal heart activity. In this study we will examine how different antiarrhythmic compounds bind to a protein ion channel, called KCNQ1, that is able to conduct potassium and has a vital role in maintaining the normal electrical activity of the heart, especially during the relaxing phase of the heartbeat. This ion channel is like a tiny machine that alters its structure in response to changes in the heart cell voltage. However, until recently we have not been able to study these structures as the ion channels are embedded in the fatty cell membranes that make them resistant to X-ray crystallography methods. Recently, though we have been using high resolution microscopy to visualize the channels in their different states during the cardiac cycle. We want to do this because an understanding of how specific compounds can bind to the distinct shapes that the ion channel protein makes as it goes from rest to activated and back again gives us critical information to design new and more specific drugs to modulate the ion channel activity and treat diseases such as long QT syndrome and atrial fibrillation. The studies will be complemented with computer simulations to gain a greater understanding of how the protein functions when exposed to ion channel modulating drugs, during all stages of the cardiac cycle.