The candidate's long term goal is to investigate mechanisms responsible for cardiac arrhythmias, to diagnose and treat patients suffering from cardiac arrhythmias, and to facilitate the application of knowledge gained from basic science to the treatment of patients with cardiac arrhythmias. Early Afterdepolarizations (EADs) due to L-type Ca2+ current (Ica-L) are a probable trigger for ventricular arrhythmias associated with prolonged action potential (AP) repolarization. AP prolongation is the likely basis for arrhythmias due to drugs, congenital disease, and heart failure. The multifunctional Ca2+/calmodulin-dependent protein kinase II (CAM kinase) augments Ica-L in response to increased intracellular Ca2+([Ca2+]I). Increased [Ca2+]I occurs during EASD, so CaM kinase may act as a proarrhythmic signaling molecule for EADS. After initial activation, CaM kinase activity becomes independent of [Ca2+]I, hence, CaM kinase may act as both a [Ca2+]I-dependent and a [Ca2+]I-independent positive feedback effector for Ica-L and EADs. The following specific aims will be used to test the hypothesis that CaM kinase is a proarrhythmic signaling molecule for EADS: 1. Determine the role of intracellular Ca2+ and L-type Ca2+ current in early afterdepolarizations in cardiac cells with prolonged action potentials. 2. Determine the effect of multifunctional Ca2+/calmodulin - dependent protein kinase II inhibition on L-type Ca2+ current and early afterdepolarizations. 3. Determine if [Ca2+]I-independent multifunctional Ca2+/calmodulin - dependent protein kinase II activity increases during early afterdepolarizations. EADs will be studied in isolated ventricular myocytes with prolonged action potentials, using current clamp and whole cell mode voltage clamp with action potential wave forms, under conditions where Ica-L is measured and [Ca2+]I is controlled by flash photolysis of photolabile Ca2+ chelators. Cardiac cells from a recently engineered MinK gene knock out mouse, will also be available for these studies. This study will take place under the guidance of Dr. Dan Roden at Vanderbilt University. Dr. Roden directs an active arrhythmia research program with established expertise in cardiac molecular electrophysiology.
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