短QT综合征（SQTs）可促进房颤和室速的发生，是导致心源性猝死的重要原因，但其发病机制仍不明确。我们前期研究表明：心肌特异性过表达转化生长因子III型受体（TGFBR3）小鼠出现SQTs表型，且对电刺激触发的房颤易感性增强；对临床房颤患者、OSA诱发的房颤犬模型的心肌标本检测发现TGFBR3和内向整流钾电流IK1亚基Kir2.1蛋白表达均显著增加。 本申请拟阐明TGFBR3促SQTs的分子机制——心（房、室）肌细胞TGFBR3与GIPC1偶联增强GIPC1的招募功能，GIPC1通过其PDZ结构域与Kir2.1蛋白的PDZ识别模序（Motif）相结合，调节IK1钾通道在细胞膜上的稳定性和转运（trafficking），促进该通道的开放，导致SQTs的产生。本研究将首次证明TGFBR3是SQTs调控的关键分子，丰富对Kir2.1钾通道转运机制的新认识，并为房颤/室速等心律失常防治提供新策略。

Short QT interval syndrome (SQTs) is one of the most important reasons of sudden cardiac death, because it can promote the development of atrial fibrillation (AF) and ventricular tachycardia; however, its mechanism has not been fully clarified. Our previous investigation showed that cardiac-specific transgenic expression of transforming growth factor-β receptor III (TGFBR3) independently led to phenotype of SQTs in mice, the TGFBR3 transgenic mice were more sensitive to developing into AF after electric stimuli compared with their wild type littermate controls. The cardiac tissue from AF patients and OSA-induced AF canines showed significantly higher protein expression level of TGFBR3 and the subunit Kir2.1 of inward rectifier potassium current (IK1). Therefore, this proposal aims to clarify the molecular mechanisms of TGFBR3 in the development of SQTs through coupling with GIPC1 and then enhance its recruitment function. We hypothesize that GIPC1 through its PDZ domain binds to the PDZ motif of Kit2.1, regulates the stability and trafficking of IK1 potassium channel, promotes the channel activation and subsequently leads to SQTs. This investigation will firstly demonstrate that TGFBR3 is one of the key regulators of SQTs, fulfill the knowledge about the trafficking mechanism of Kir2.1 potassium channel, and then provide novel strategy for the prevention and therapy of arrhythmia, for instance, AF, ventricular tachycardia, etc.