Molecular basis of junctophilin-2 regulation of ryanodine receptor-2 in cardiomyocytes

钙离子循环决定心脏功能和心肌细胞的存活/死亡。钙循环受肌浆网钙释放单位的调节。这个装置保持钙循环正常，这是心脏收缩和放松的一个重要过程。然而，在心肌细胞中钙释放单位动态平衡的本质还没有完全被理解。 本研究旨在研究一种名为“Junctophlin-2”的结构蛋白如何维持心肌细胞钙释放单位的正常。具体地说，我们将研究连接素-2是如何保护心肌细胞中另一种称为“连接素”的蛋白质的。Junctin是钙释放单位的重要组成部分。如果没有连接素，钙释放单位不能正常工作，增加肌浆网钙离子的释放，导致心肌细胞钙稳态的紊乱。钙循环失调会损害心脏功能。因此，我们还将研究连接素的保护是否是连接素-2保持钙释放单位正常工作的机制。 本研究将为研究连接素-2在钙释放单位中对连接素的调控及其对钙循环的影响提供分子基础。因此，我们的发现将显著增加我们对钙循环本质的理解，这对于阐明心脏生物和病理生理状态的机制是至关重要的。

Calcium ion cycling determines heart function and heart muscle cell survival/death. The calcium cycling is regulated by calcium release unit of sarcoplasmic reticulum. This unit keeps calcium cycling properly, a process important for heart contract and relaxation. However, the nature of calcium release unit homeostasis has not been fully understood in heart muscle cells. This study is proposed to investigate how a structural protein called "junctophilin-2" maintains the normality of calcium release unit in heart muscle cells. Specifically, we will examine how junctophilin-2 protects another protein called “junctin” in heart muscle cells. Junctin is an important component of calcium release unit. Without junctin, calcium release unit does not work properly and increases calcium ion release from sarcoplasmic reticulum, leading to perturbation of calcium homeostasis in cardiomyocytes. Dysregulation of calcium cycling damages heart function. Thus, we will also examine whether protection of junctin is a mechanisms by which junctophilin-2 keeps calcium release unit working properly. This study will provide molecular basis for junctophilin-2 regulation of junctin in calcium release unit and its influence on calcium cycling. Thus, our findings will significantly increase our understanding of the nature of calcium cycling, which is critical for elucidating mechanistic insights in the biological and pathophysiological states of the heart.