Role of Desmosomes in Cardiac Electrical Function

桥粒在心脏电功能中的作用

• 批准号: 8041749
• 负责人: Mario Delmar
• 金额: $ 55.03万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8041749
• 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

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.

描述（由申请人提供）：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，以便单个肌细胞的工作转化为器官的泵功能。连接复合物优先位于闰盘内肌细胞之间的端端接触部位。闰盘中还存在传统上不被认为是“连接”的分子，即不参与在相邻细胞之间提供物理连续体的分子。在这里，我们寻求更好地了解机械连接、间隙连接和电压门控钠通道（VGSC）复合体之间的关联。实验源于我们的观察，即桥粒蛋白 plakophilin-2 (PKP2) 表达的丧失会导致钠电流振幅降低和动力学变化。我们的初步数据进一步表明，已知与心脏钠通道蛋白相关的细胞骨架衔接蛋白锚蛋白-G (ankG) 在功能上与 PKP2 和间隙连接蛋白 connexin43 (Cx43) 相互作用。因此，我们测试了总体假设，即机械连接与电压门控钠通道复合物之间存在功能上的相互依赖性，并且两个组件内的分子可以影响心脏中间隙连接介导的细胞间通讯。具体目标是： 1：表征锚蛋白-G 与间隙连接蛋白 connexin43 的相互作用。图 2：研究锚蛋白-G 与参与细胞间机械耦合的蛋白质的相互作用。图3：评估钠电流对桥粒蛋白表达的依赖性。我们推测，发生在闰盘上的这种“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，而且与影响闰盘完整性的后天性疾病（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至关重要。心脏中的细胞通过机械和电相互作用。在这里，我们将研究对机械功能重要的分子变化如何影响电气行为。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出现严重的心律失常，从而导致猝死。