心房肌细胞钙稳态异常是房颤发生的重要机制之一。肌浆网钙通道RyR2稳定性下降导致钙泄漏是钙稳态异常的重要原因。我们前期研究发现，房颤患者心房肌JPH2基因及蛋白表达水平均明显降低，伴胞内钙火花等异常钙释放事件发生频率明显增多。提示JPH2可能参与调节RyR2关闭状态的稳定性，而其本身可被钙蛋白酶calpain-I酶解。本项目在业已建立的快速起搏心房兔房颤模型上，采用受激发射损耗显微技术、单颗粒冷冻电子显微技术、全细胞膜片钳、激光共聚焦及平面脂质膜单通道技术等手段，从整体、细胞及超微结构水平，进一步探讨calpain-I对JPH2表达变化的影响，重点研究JPH2对RyR2蛋白空间构象、单通道开放频率、肌浆网异常钙释放事件以及细胞延迟后除极（DAD）等异常电触发活动的调控机制，明确JPH2在稳定RyR2通道、影响钙泄漏中的作用及可能机制。本研究有助于阐明房颤发生的可能机制，为其治疗提供新思路。

Atrial cardiomyocyte calcium homeostasis abnormality, which is reported mainly due to the increased sarcoplasmic reticulum (SR) Ca2+ leak (Ca2+ spark or Ca2+ wave) from “leaky” Ca2+ release channel ryanodine receptor (RyR2), is one of the most important mechanisms in atrial fibrillation (AF) initiation and progression. Previous studies showed the role of junctophilin-2 (JPH2), a membrane-coupling protein, in stabilizing RyR2, and calcium dependent neutral proteases calpain-I is activated as the cytosolic calcium increases, leading to cytoplasmic or membrane protein proteolysis. Our previous works have documented a down-regulated expression of JPH2 in both mRNA and protein levels in the atrial myocardium of persistent AF patients with an increased Ca2+ spark frequency. Thus, we hypothesized that JPH2 degradation, induced by activated calpain-I, can modulate RyR2 gating and SR Ca2+ leak leading to AF..This study is designed to elucidate whether calpain-I is involved in the degradation of JPH2 proteins, and furthermore, to explore the mechanism of JPH2 on RyR2 gating instability (single RyR2 channels open probability [RyR2 Po], Ca2+ spark or Ca2+ wave), subsequently the effect of JPH2-mediated regulation of RyR2 on arrthymogenic trigger activity (delayed after depolarization [DAD]) and the AF incidence, with stimulated emission depletion microscopy (STED), single-particle cryo-EM, single channel recordings, whole-cell patch clamp as well as laser confocal Ca2+ imaging techniques in the established rapid atrial pacing rabbit AF model and isolated rabbit atrial myocytes. The results of this research will help understand the mechanism of AF and provide new vision on the optimized therapeutic options based on the mechanistic insights.