心肌特异性过表达TGFBR3启动Kir2.1钾通道运输促短QT综合征的作用与分子调节机制

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.

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。

我们既往研究表明转化生长因子III型受体（TGFBR3/TβRIII/TGFβR3）促进心肌肥厚的发生。心脏特异性过表达TβRIII转基因小鼠出现短QT综合征，房颤易感性增加的表型，本项目深入研究TβRIII致QT间期缩短、房颤易感性增加的机制，取得如下原创性研究结果：①TβRIII通过GIPC1蛋白与钾离子通道Kir2.1蛋白相互作用，稳定其在心肌细胞膜上表达，进而引起房颤易感性增加；GIPC1通过C端PDZ结构域与Kir2.1蛋白PDZ识别基序相结合，进而促进Kir2.1蛋白向心肌细胞膜转位。②TβRIII还可通过ARRDC4促进Kir2.1泛素化修饰，稳定其细胞膜水平，抑制其降解。③拓展研究了GIPC1蛋白在心脏疾病中的作用，发现心脏GIPC1敲除引起心脏病理性重构，过表达GIPC1可抑制异丙肾上腺素（ISO）诱导的心脏重构，其机制与GIPC1/β1-AR相互作用进而抑制β1-AR泛素化，稳定其表达水平有关。我们的上述研究揭示了TβRIII及其调控的下游分子在心脏病理性重构和心律失常中的作用，为这类疾病发病机制提供理论依据和潜在干预靶点。

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