Role of Desmosomes in Cardiac Electrical Function

桥粒在心脏电功能中的作用

• 批准号: 8762968
• 负责人: Mario Delmar
• 金额: $ 49.32万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762968
• 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.

细胞间通信对于适当的心脏功能至关重要。机械和 电活动需要同步，以便单个肌细胞的工作 转换为器官的泵送功能。连接络合物优先 驻留在插入式椎间盘内肌细胞之间的端端接触部位。还 插入式椎间盘的居民是传统上不被认为是“交界”的分子 也就是说，不参与相邻细胞之间提供物理连续性。这里， 我们寻求更好地理解机械连接，差距之间的关联 连接和电压门控钠通道（VGSC）复合物。实验茎 根据我们的观察，脱褐色蛋白质plakophilin-2的表达丧失 （PKP2）导致幅度降低和钠电流动力学的变化。 我们的初步数据进一步表明细胞骨架衔接蛋白arnkyrin-g （ANKG），已知与心脏钠通道蛋白相关的已知 功能与PKP2和间隙连接蛋白连接43（CX43）相互作用。 因此，我们检验了总体假设，即具有功能相互依存 电压门控钠通道复合物的机械连接 两个组分内的分子都会影响间隙连接介导的细胞间 心脏的交流。具体目的是：1：表征的相互作用 Ankyrin-G与间隙连接蛋白连接蛋白43。 2：研究倒数 Ankyrin-G与蛋白质与细胞之间机械耦合有关的蛋白质的相互作用。 3： 评估钠电流对脱发体表达的依赖性 蛋白质。我们推测这种“其他”机电耦合发生在 插入式椎间盘，不仅与对心律失常发生的理解有关 罕见的遗传疾病，但在获得的疾病（心肌病）中也影响了 插入式圆盘的完整性。