Connexons in Cardiovascular Cell Communication

描述（由申请人提供）：房颤是人类最常见的心律失常，具有显著的发病率和死亡风险增加。缝隙连接通道可能在心房颤动的稳定和维持中发挥重要作用，因为心房颤动与心房肌细胞之间的连接重塑和电传导改变有关。这些通道（由连接蛋白亚基CX组成）提供了离子和小分子直接通过细胞间的途径，促进心脏电传导和心血管细胞对细胞内信号的反应协调。两种主要的连接蛋白（CX 40和CX 43）在心房中表达。大量研究表明，CX40的改变（包括水平降低、分布异质性和突变）有助于房颤的发病机制。提出了一系列的实验：（1）测试的假设，CX40单独或相对于CX43的改变存在于心房组织中的房颤患者，和（2）使用表达系统来测试这些改变如何影响细胞间通讯。实验结果将有助于阐明缝隙连接在心律失常中的作用。他们还将阐明缝隙连接介导的细胞间通讯的基本细胞生物学和生理学。 公共卫生相关性：心脏的正常功能取决于细胞之间的电流通道，并由称为间隙连接的结构中包含的细胞间通道促进。电传导的紊乱导致心律失常，如心房纤颤。我们的研究将阐明亚基间隙连接蛋白的异常如何导致心律失常，如心房颤动。

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.