CELLULAR MECHANISMS OF DELAYED AFTERDEPOLARIZATIONS

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The goal of this proposal is to elucidate the specific membrane currents and intracellular ionic fluctuations which produce delayed afterdepolarizations (DADs). Delayed afterdepolarizations are transient depolarizations of the cell membrane potential which occur after completion of repolarization from a preceding impulse. DADs thereby sustaining the triggered rhythmic activity that is believed responsible for certain types of clinically observed arrhythmias. DADs have been demonstrated in a variety of cell types including diseased human atrial and ventricular fibers studied in vitro and under a variety of conditions that cause abnormal intracellular calcium fluctuations ([Ca2+]i). However, the precise relation between abnormal [Ca2+]i fluctuations and the transient inward membrane currents (ITi) thought to generate DADs is not known. Combining innovative Ca2+ imaging techniques with established whole-cell voltage clamp methods, the proposed research tests a comprehensive hypothesis that relates these ITis to disorders in the regulation of [Ca2+]i fluctuations are spatially non-homogeneous and temporally asynchronous, b) [Ca2+]i fluctuations activate local membrane currents, c) the temporal synchronization of both [Ca2+]i fluctuations and their local currents by an action potential generates a ITi. Using cell pairs, the research plan would also clarify the conditions under which spontaneous [Ca2+]i; fluctuations and local ITis are transmitted between cells to produce the synchronized current activation of a DAD. This project will provide the fundamental quantitative data on [Ca2+]i fluctuations for the understanding of surface membrane currents. By the application of these quantitative methods to electrically coupled cell paris, this project will also provide direct information on how the ionic and current events observed in isolated cells are influenced and modified by intercellular communication mediated through gap junctions. This approach would bridge the gap between isolated cell studies and whole tissue models and would also allow the testing of mathematical formulations of impulse transfer between cells and through tissues.