Connexons in Cardiovascular Cell Communication

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DESCRIPTION (provided by applicant): Atrial fibrillation is the most common arrhythmia in man and confers a significant morbidity and increased risk of mortality. Gap junction channels are likely to play significant roles in the stabilization and maintenance of atrial fibrillation, since atrial fibrillation is associated with remodeling of connections between atrial myocytes and altered electrical conduction. These channels (made of connexin subunits, CX) provide a pathway for direct intercellular passage of ions and small molecules facilitating cardiac electrical conduction and coordination of the responses of cardiovascular cells to intracellular signals. Two major connexins (CX40 and CX43) are expressed in the atrium. A variety of provocative studies suggest that alterations of CX40 (including reduced levels, heterogeneity of distribution, and mutations) contribute to the pathogenesis of atrial fibrillation. A series of experiments are proposed: (1) to test the hypothesis that alterations of CX40 alone or relative to CX43 are present in atrial tissue from patients with atrial fibrillation, and (2) to use expression systems to test how these alterations can affect intercellular communication. The results of the proposed experiments will clarify the role of gap junctions in cardiac arrhythmias. They will also elucidate the basic cellular biology and physiology of gap junction-mediated intercellular communication. PUBLIC HEALTH RELEVANCE: The normal functioning of the heart depends on passage of electrical current between cells and is facilitated by intercellular channels contained within structures known as gap junctions. Disturbances of electrical conduction lead to abnormal heart rhythms such as atrial fibrillation. Our studies will clarify how abnormalities of the subunit gap junction proteins lead to arrhythmias such as atrial fibrillation.