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.

细胞间通讯对于正常的心脏功能至关重要。机械和 电活动需要同步，以便各个肌细胞的工作 转化为器官的泵功能。优先选择连接复合体 位于闰盘内肌细胞之间末端接触的部位。还 驻留在闰盘上的是传统上不被认为是“连接”的分子， 也就是说，不参与提供相邻小区之间的物理连续体。这里， 我们寻求更好地理解机械接头、间隙之间的关联 连接和电压门控钠通道（VGSC）复合体。实验干 根据我们的观察，桥粒蛋白 plakophilin-2 表达缺失 (PKP2) 导致钠电流的振幅降低和动力学变化。 我们的初步数据进一步表明细胞骨架衔接蛋白锚蛋白-G (ankG)，已知与心脏钠通道蛋白相关， 与 PKP2 和间隙连接蛋白 connexin43 (Cx43) 发生功能性相互作用。 因此，我们检验了总体假设，即各组织之间存在功能上的相互依赖性。 与电压门控钠通道复合体的机械连接，并且 两种成分中的分子都可以影响间隙连接介导的细胞间 沟通在心里。具体目标是： 1：表征相互作用 锚蛋白-G 与间隙连接蛋白 connexin43。 2：研究倒数 锚蛋白-G 与参与细胞间机械耦合的蛋白质的相互作用。 3： 评估钠电流对桥粒表达的依赖性 蛋白质。我们推测这种“其他”机电耦合发生在 闰盘，可能不仅与理解心律失常发生有关 罕见的遗传性疾病，但也有影响的后天性疾病（心肌病） 闰盘的完整性。