Mechanisms of Gap Junction Regulation

摘要： 缝隙连接是一种完整的膜蛋白，它能使离子和低分子离子在细胞质中直接交换 相邻细胞之间的分子质量代谢物。它们为繁殖和/或扩增提供了一条途径 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 参与生长调节和发育。通过缝隙连接的细胞间通讯功能障碍 与许多人类疾病有牵连。这个项目的目标是使用一个多学科的 确定负责Cx43和Cx45功能的关键内在调控机制的方法。 中心假设是连接蛋白发散CT结构域中独特的分子间相互作用 影响缝隙连接调节。更具体地说，我们假设在心肌梗死后， Cx43和Cx45的调控涉及其CT结构域的特异性磷酸化和蛋白质相互作用。这个 这一建议的意义在于发现了如何调节由CT结构域介导的相互作用 将打开一扇门，以采取策略来改善失败时连接蛋白调节改变的病理影响 心。提出了以下具体目标来调查这一概念：1)是什么驱使Cx43远离GAP 在体外和小鼠心肌梗死模型中连接/插入盘？2)是什么推动了Cx45 缝隙连接/间盘定位及Cx45在心肌梗死后左室肥厚中的表达 心肌梗死是导致心律失常的底物？在这个项目完成后，我们希望描述小说 磷酸化和蛋白质伙伴调控Cx43和Cx45功能的机制和策略 在衰竭的心脏中，Pyk2、Src和Cx45上调的病理效应可能会减轻。

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.