心房电重构是心房颤动（AF）发生和维持的重要机制之一。心脏上的小电导钙激活钾通道（SK2）因其具有偶联胞内钙和膜电位、心房相对特异性表达等特点，被认为是AF的潜在治疗靶点。前期研究和文献表明，心房快速起搏促进SK2通道蛋白向细胞膜转运，而AF时SK2电流上调但其总体蛋白水平却下调，提示SK2通道蛋白在AF时向细胞膜转运过程可能存在异常，然其机制未明。本项目提出假说：AF时SK2通道蛋白在转运蛋白VAMP2等作用下，由胞浆向细胞膜的转运、膜上SK2通道蛋白的内吞及内吞后再循环到细胞膜的过程出现异常，引起AF时SK2通道的功能改变。为此，本项目以AF患者心房肌、犬房颤模型结合工具细胞为研究对象，采用电生理、细胞和分子生物学等技术，系统研究心房肌SK2通道蛋白三个转运过程的时空特性与调控规律及其在AF发生和维持中的改变机制。从一个新的角度阐释SK2通道与AF的相互关系，为AF的治疗提供新的思路。

Atrial electrical remodeling (AER) is an important mechanism for the occurrence and maintenance of Atrial fibrillation (AF) . Small conductance calcium-activated potassium channels (SK2), which has been found in the heart for ten years, is considered a potential therapeutic target for AF, due to its coupling with intracellular calcium and membrane potential, and the relative atrial specific expression of this channel. Previous reports including ours showed that rapid atrial pacing promoted the trafficking of SK2 channels to the cell membrane, increased SK2 currents but decreased the total protein level of SK2 in human AF, suggesting that the trafficking of SK2 protein towards cell membrane is damaged in AF. However, the underlying mechanism is still unknown. This project aims to test the hypothesis that SK2 protein turnover, including trafficking to the membrane, endocytosis and reinsertion to membrane (recycling), are abnormal in AF, and further to investigate the underlying mechanisms, using models of human AF, canine AF and engineered HEK293 cells, and multiple techniques including electrophysiology, cellular and molecular biology. The project may help to illuminate the important role of SK2 channel in AF at a new viewpoint and provide new strategy for the treatment of AF.