Mechanisms of Gap Junction Regulation

摘要： 缝隙连接是一种完整的膜蛋白，它能使细胞内的离子直接交换， 相邻细胞之间的分子量代谢物。它们提供了一条传播和/或扩增 由细胞因子、生长因子和其他细胞信号分子触发的信号转导级联 参与生长调节和发育。通过间隙连接的细胞间通讯功能障碍 与许多人类疾病有关。该项目的目标是使用多学科 方法来确定负责Cx43和Cx45功能的关键内在调节机制。 中心假设是，独特的分子间相互作用内的分歧CT域的连接蛋白 影响间隙连接调节。更具体地说，我们假设心肌梗死后， Cx43和Cx45的调节涉及其CT结构域的特异性磷酸化和蛋白质相互作用。的 该建议意义在于发现了如何调节由CT结构域介导的相互作用 将打开大门的战略，以改善病理影响的改变连接蛋白调节的失败， 心提出以下具体目标来研究这个概念：1）是什么驱使Cx43远离间隙 连接/闰盘在体外和小鼠模型的心肌梗死？2）什么促进了Cx45 心肌梗死后左室肥厚心肌间隙连接/闰盘定位及Cx45表达的研究 梗死是一种致瘤基质？在这个项目完成后，我们希望描述小说 磷酸化和蛋白质伴侣调节Cx43和Cx45功能的机制和策略， 其可以减轻衰竭心脏中Pyk 2、Src和Cx45上调的病理作用。

Abstract: Gap junctions are integral membrane proteins that enable the direct cytoplasmic exchange of ions and low molecular-mass metabolites between adjacent cells. They provide a pathway for propagating and/or amplifying the signal transduction cascades triggered by cytokines, growth factors, and other cell signaling molecules involved in growth regulation and development. Dysfunctional intercellular communication via gap junctions has been implicated in causing many human diseases. The objective of this project is to use a multi-disciplinary approach to identify the key intrinsic regulatory mechanisms that are responsible for Cx43 and Cx45 function. The central hypothesis is that unique intermolecular interactions within the divergent CT domain of connexins affect gap junction regulation. More specifically, we hypothesize that after myocardial infarction, differential regulation of Cx43 and Cx45 involves specific phosphorylations and protein interactions of their CT domain. The significance of this proposal is that discovery of how interactions mediated by the CT domain can be modulated would open the door to strategies to ameliorate pathological effects of altered connexin regulation in the failing heart. The following Specific Aims are proposed to investigate this concept: 1) What drives Cx43 away from gap junctions/intercalated discs in vitro and in a murine model of myocardial infarction? and 2) What promotes Cx45 gap junction/intercalated disc localization and is Cx45 expression in left ventricle hypertrophy after myocardial infarction an arrhythmogenic substrate? Upon completion of this project, we expect to describe novel mechanisms by which phosphorylation and protein partners regulate Cx43 and Cx45 function and strategies by which the pathological effects of Pyk2, Src, and Cx45 upregulation in failing hearts may be lessened.