Atrial fibrillation (AF) is the most common clinical arrhythmia affecting American population and is associated with a significant increase in morbidity and mortality, yet, treatment strategies have proven largely inadequate. We have employed molecular genetic and electrophysiological recordings to demonstrate the development of AF in a mouse model with null mutation of an L-type Ca channel (LTCC), Cav1.3 (alphalD), which we have shown to be highly expressed in the atria. In addition, we have unmasked a novel finding, that there is a functional crosstalk between Ca and the K channels, mainly a small conductance Ca-activated K channel (SK channel) via cytoskeletal protein, alpha-actinin2. We hypothesize that the functional crosstalk between SK channels and Ca channels occur via cytoskeletal proteins. In other words, the interacting partners may serve as bridges for the crosstalk between Ca and K channels. We further hypothesize that regional-specific sub-cellular localization of the different isoforms of LTCC's in the heart results from specific interaction of Ca channels with interacting proteins. We predict that the specific sub-cellular localization and protein-protein interactions are critical in the functional properties of the channels. Abnormalities in the functions of these ion channel proteins can result in alteration of atrial refractory period and the increase occurrences of AF. Our study will directly examine the molecular mechanisms of the functional coupling of Ca-activated K channels and Ca channels as well as differential isoform-specific subcellular localization of the Ca channels in human atria, identify the novel interacting proteins and the functional significance of the interactions. The study will have important implication in our understandings of the repolarization in atria and may provide insights into novel therapy for atrial arrhythmias, a common problem encountered in our patient population. Motivation for the proposal is extremely high since we have already obtained new evidence to show that these channels are critically important in atrial myocytes. These studies will substantially expand our understanding of the specific functions of individual Ca and K channels and how they may coordinate to mediate normal cardiac function in human. ? ? ?
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