Molecular targets in atrial fibrillation

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DESCRIPTION (provided by applicant): Atrial fibrillation is the most common sustained cardiac arrhythmia and a major source of morbidity and mortality in the US. Available antiarrhythmic drugs are often ineffective and create serious proarrhythmia because channels in the ventricle are affected. In addition, electrical remodeling due to rapid stimulation in the atrium further perpetuates the arrhythmia, contributing to its refractory nature. The goal of this proposal is to identify novel targets for the treatment of atrial fibrillation by investigating the molecular basis of an atrial-specific ultra-rapid K+ current, IKur, and the early intracellular events that trigger the remodeling process. While the Kv1.5 gene product is an important component of IKur, our preliminary data indicate that this -subunit cannot fully recapitulate IKur, and we will test the hypothesis that co-assembly of additional channel subunits and/or signaling proteins occurs in vivo. The Kv1.5 complex will be isolated from human atrium and coassembled K+ channel lpha and/or etasubunits will be identified using antibody-based methods. Following heterologous expression of the proteins identified, electrophysiologic techniques will be used to confirm if the resultant K+ current phenotype is that of IKur. An analogous strategy will be used to determine the role of A-kinase anchoring proteins (AKAPs) in the Kv1.5 signaling complex. We will also test the hypothesis generated by our preliminary data that a Kv eta subunit can function as an AKAP. Finally, our initial results indicate that chronic rapid stimulation of atrial cells in culture leads to electrical remodeling, and this system will be used to test the hypothesis that the molecular events that trigger remodeling resemble those of cardiac hypertrophy, with activation of specific intracellular signaling cascades. The knowledge gained from these studies will improve our understanding of the molecular components of atrial electrophysiology, and should lead to the development of novel targets to treat atrial fibrillation.