Junctophilins（JPs）连接可兴奋细胞的质膜和内质/肌浆网膜，形成耦联膜复合体（JMCs），在Ca2+通道信号网络调控发挥关键作用。人类JPs基因缺失或突变可影响心脏、神经等多种疾病。外界化学因素可改变JP1构象；应激情况下，心肌JP2和神经元JP3可显著下调、水解。申请人最近研究发现，胰岛β细胞表达JP3，并发现胰岛β细胞和心肌细胞均存在“JMCs-内质网-线粒体轴”，沉默Jps分别导致胰岛素释放或心肌收缩功能异常，提示存在药物通过影响JPs而致组织损伤的研究新空间。本项目拟进一步探索胰岛β细胞沉默Jps，对“JMCs-内质网-线粒体轴”完整性影响的表征，对“内质网-线粒体”间信号交流影响，及进而损伤胰岛素释放功能的调控机制，揭示其不可或缺的生命现象本质。力图阐明药物干预胰岛β细胞“JMCs-内质网-线粒体轴”完整性，所致Ca2+信号调控异常与胰岛素释放功能损伤的相关性。

Insulin secretion stimulated by glucose is closely associated with cytoplasmic Ca2+ flux and mitochondrial metabolism in pancreatic β cells. However, the relationship between both of them on insulin secretion remains undefined. Here we display an essential role of the junctophilin subtype, junctophilin 3 (JP3), in regulating insulin secretion in mouse primary pancreatic β cells. JP3 contributing to insulin release is largely dependent on the junctional membrane complexs (JMCs)-endoplasmic reticulum (ER)-mitochondria axis integrity. Knockdown of Jph3 disturbs spatial organization of the axis, which, in turn, might affect mitochondrial function. We expect that Jp3 knockdown does not result in ER stress, instead, suppresses the mitofusin 2 (Mfn2) expression trigged by RyR-dependent Ca2+ flux through reducing an Mfn2 regulator, Pgc-1α, mRNA expression and nuclear translocation. This project is expected to reveal a novel role that JPH regulating insulin secretion by manipulating spatial organization of JCMs-ER-mitochondria axis integrity via a RyR-Ca2+ flux/Pgc-1α activation/Mfn2 expression signaling pathway.