缝隙连接蛋白43（Cx43）是构成心室缝隙通道关键蛋白，维系心脏泵功能和电活动的协调统一及心肌细胞稳态。Cx43重构（去磷酸化，及分布和表达改变）发生在多种心脏疾病早期，是造成心脏泵功能和电活动失常的重要病因，以及致心肌细胞死亡的危险因素，但Cx43重构的机制不清。前期发现：Cx43丝氨酸282位点磷酸化（pS282）下调，导致1）心肌细胞间通讯障碍和心律失常；2）心肌凋亡和纤维化；3）Cx43由心肌细胞端位分布至侧面；4）Cx43表达减少，提示Cx43-pS282改变可能与Cx43重构有关。本项目拟在基因动物/心肌细胞/多肽片段研究：1）Cx43重构继发于下调的pS282；2）pS282下调如何诱导Cx43重构；3）干预该位点抑制Cx43重构的可能性，进而阐释心肌Cx43-S282磷酸化在Cx43生命周期中的生理作用及其病理生理意义，为Cx43重构提供新的分子机制和潜在的干预靶点。

Connexin43 (Cx43) is the main connexin subtype in ventricles, regulating myocardium beats and contractility, as well as cardiomyocyte homeostasis. Cx43 remodeling, including Cx43 dephosphorylation, Cx43 lateralization distribution and expression reduction, often occurs at the early stage of several heart diseases, such as ischemia heart, heart failure and arrhythmias. It is the critical cause of cardiac dysfunction and electricity disorders, and one the risk factors of cardiomyocyte death. However, the mechanism(s) underlying Cx43 remodeling is quite unclear. Our previous studies in heart have found that Cx43-serine 282 (S282) dephosphorylation caused 1) blockade of intercellular communication and arrhythmias; 2) cardiomyocyte apoptosis and fibrosis; 3) Cx43 distribution from the end of myocyte to the lateral sides; 4) Cx43 expression reduction. All these observations suggest that S282 dephosphorylation may be involved in the formation of Cx43 remodeling. Here, in this project we use S282 mutated mice and cultured cardiomyocytes and investigate 1) Cx43 remodeling is caused by deficient S282 phosphorylation; 2) how S282 dephosphorylation causes Cx43 remodeling; 3) whether the intervention of Cx43-S282 dephosphorylation can prevent Cx43 remodeling. Therefore, by performing these studies we intend to evaluate the important roles of Cx43-S282 phosphorylation in regulating Cx43 life cycle and cardiomyocyte homeostasis and in the progress of heart diseases as well, providing a novel molecular mechanism for Cx43 remodeling and potential protective target for heart injury.