Role of Desmosomes in Cardiac Electrical Function

桥粒在心脏电功能中的作用

• 批准号: 8389874
• 负责人: Mario Delmar
• 金额: $ 57.76万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8389874
• 关键词: Adaptor Signaling Protein; Address; Adherens Junction; Affect; Ankyrins; Arrhythmia; Behavior; Cadherins; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Code; Complex; Connexin 43; Connexins; Coupling; Data; Dependence; Desmosomes; Diagnostic; Disease; Functional disorder; GTP-Binding Proteins; Gap Junctions; Genes; Heart; Impairment; Individual; Inherited; Intercalated disc; Ions; Kinetics; Lead; Link; Location; Macromolecular Complexes; Mechanics; Mediating; Molecular; Muscle Cells; Mutation; Myocardium; Organ; Organelles; Pathway interactions; Patients; Population; Proteins; Pump; Role; Site; Sodium; Sodium Channel; Sudden Death; Syndrome; Testing; Therapeutic; Triad Acrylic Resin; Work; intercellular communication; plakophilin 2; research study; small molecule; sodium channel proteins; stem; voltage

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.

细胞间的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，以便单个心肌细胞的工作 转化为器官的泵送功能。优先考虑连接络合物 位于间盘内肌细胞之间的端端接触部位。也是 位于插入盘上的是传统上不被认为是“连接的”的分子， 也就是说，不涉及在相邻小区之间提供物理连续体。这里, 我们试图更好地理解机械连接和间隙之间的联系 结和电压门控钠通道(VGSC)复合体。实验茎 根据我们的观察，桥粒蛋白Plakophlin-2的表达缺失 (PKP2)导致钠电流幅度降低和动力学改变。 我们的初步数据进一步表明，细胞骨架适配器蛋白ankyrin-G (AnkG)，已知与心脏钠通道蛋白有关， 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 与电压门控钠通道复合体的机械连接，以及 两个组分中的分子都可以影响缝隙连接介导的细胞间 心与心的沟通。具体目标是：1：描述 Ankyrin-G与缝隙连接蛋白Cx43结合。2：研究相互作用 锚蛋白-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 蛋白质。我们推测这种“另一种”机电耦合，发生在 间盘，可能不仅与了解心律失常的发生有关。 罕见的遗传性疾病，但也在后天条件下(心肌病)影响 间盘的完整性。