Grant: Operating Grant

Heartbeats are controlled by electrical impulses generated by specialized proteins in the cell membrane called ion channels. Dysfunction of ion channels causes irregular heartbeats (cardiac arrhythmias) which can lead to sudden death. Therefore, ion channels are primary targets for anti-arrhythmic therapies. The overall activity of a type of ion channel in a cell is determined by the function of a single channel and the total number of channels. While the function and modulation of existing ion-channels have been extensively studied, little is known about how the number of ion channels on the cell membrane is regulated. The number of channels in a cell (channel density) is determined by both degradation (destruction) and synthesis (construction). This application will study how cells degrade ion channels and what diseases are caused by over-degradation of ion channels in the heart. We will focus on one type of channel in the heart called HERG which passes potassium ions. The HERG channel will be expressed in a cell line for detailed studies to find which cellular molecules are critical for the channel degradation. We will test a novel idea that genetic defects (mutations) in an HERG-interacting protein called caveolin-3 reduce hERG density and cause cardiac disorders. We will also study the channels in heart cells to test our hypothesis. This proposal is based on our ongoing research. We recently discovered that the HERG channel density is regulated by blood potassium concentrations. The present research will extend our research program by addressing how HERG channels are degraded under normal (physiological) and abnormal (pathophysiological) conditions. We have obtained substantial preliminary data to support our proposed research. Thus, we have both experience and techniques to accomplish the proposed work, which will generate information important for developing new strategies to treat cardiac arrhythmias by regulating ion channel density.