Role of Desmosomes in Cardiac Electrical Function

描述(申请人提供)：细胞间通讯对于正常的心脏功能是必不可少的。机械和电活动需要同步，这样单个心肌细胞的工作才能转化为器官的泵送功能。连接复合体优先位于间盘内肌细胞之间的端端接触部位。同样驻留在间盘的还有传统上不被认为是“连接的”的分子，也就是说，不参与提供相邻细胞之间的物理连续体。在这里，我们试图更好地理解机械连接、缝隙连接和电压门控钠通道(VGSC)复合体之间的联系。实验源于我们观察到的桥粒蛋白Plakopilin-2(PKP2)的表达缺失导致钠电流的幅度降低和动力学改变。我们的初步数据进一步表明，与心脏钠通道蛋白相关的细胞骨架接头蛋白ankyrin-G(ankyrin-G)在功能上与PKP2和缝隙连接蛋白43(Cx43)相互作用。因此，我们检验了总体假设，即机械连接与电压门控钠通道复合体之间存在功能上的相互依赖，并且两个组件中的分子都可以影响缝隙连接介导的心脏细胞间通讯。具体目的是：1：研究Ankyrin-G与缝隙连接蛋白Cx43的相互作用。2：研究Ankyrin-G与参与细胞间机械偶联的蛋白质的相互作用。3：探讨钠电流对桥粒蛋白表达的依赖性。我们推测，这种发生在间盘的“其他”机电耦合，可能不仅与理解罕见遗传性疾病的心律失常发生有关，而且与影响间盘完整性的获得性条件(心肌病)有关。 公共卫生相关性：细胞间通讯对于正常的心脏功能是必不可少的。心脏中的细胞相互作用，既有机械的，也有电子的。在这里，我们将研究分子的变化对机械功能的重要性，以及如何影响电行为。这些研究可能有助于理解为什么患有心肌疾病的患者有时会患上导致猝死的严重心律失常。

DESCRIPTION (provided by applicant): Intercellular communication is essential for proper cardiac function. Mechanical and electrical activity need to be synchronized so that the work of individual myocytes transforms into the pumping function of the organ. Junctional complexes preferentially reside at the site of end-end contact between myocytes, within the intercalated disc. Also resident to the intercalated disc are molecules not traditionally considered "junctional," that is, not involved in providing a physical continuum between neighboring cells. Here, we seek a better understanding of the association between mechanical junctions, gap junctions and the voltage-gated sodium channel (VGSC) complex. Experiments stem from our observations that loss of expression of the desmosomal protein plakophilin-2 (PKP2) leads to a decrease in amplitude and a shift in kinetics of the sodium current. Our preliminary data further indicate that the cytoskeletal adaptor protein ankyrin-G (ankG), which is known to associate with the cardiac sodium channel protein, functionally interacts with PKP2 and with the gap junction protein connexin43 (Cx43). Thus, we test the overall hypothesis that there is a functional interdependence of the mechanical junctions with the voltage-gated sodium channel complex, and that molecules within both components can influence gap junction mediated intercellular communication in the heart. Specifics Aims are: 1: To characterize the interaction of ankyrin-G with the gap junction protein connexin43. 2: To study the reciprocal interaction of ankyrin-G with proteins involved in mechanical coupling between cells. 3: To assess the dependence of the sodium current on the expression of desmosomal proteins. We speculate that this "other" electromechanical coupling, occurring at the intercalated disc, may be relevant not only in the understanding of arrhythmogenesis in rare inherited diseases, but also in acquired conditions (cardiomyopathies) affecting the integrity of the intercalated disc. PUBLIC HEALTH RELEVANCE: Intercellular communication is essential for proper cardiac function. Cells in the heart interact with each other both mechanically and electrically. Here we will study how changes in molecules important for mechanical function, also affect electrical behavior. These studies may help in the understanding of why patients with diseases of the heart muscle, sometimes suffer severe cardiac arrhythmias that cause sudden death.