Mechanisms of couplon-linked skeletal muscle myopathies

骨骼肌横管中的L钙通道(CaV1.1)、兰尼定受体(RyR_1) 肌浆网(SR)和钙调蛋白(Casq1)在交界性SR(JSR)腔内是肌浆网(JSR)的关键成分。 一种被称为偶联的大分子复合体，它调节兴奋-收缩耦合(ECC)。基因突变 RyR1、CaV1.1和Casq1是人类肌病的基础，具有重叠的病理特征。除了 丹曲林用于恶性高热，目前还没有FDA批准的针对这些肌病的干预措施。老鼠 随着CaV1.1(E1014K)、RyR1(I4895T)和Casq1(D244G)的突变，肌肉疾病的严重性会增加 随着年龄的增长，其肌肉表现为Casq1错误定位和持续的内质网应激。此应用程序旨在 阐明CaMKII依赖途径中突变相关改变导致ER的机制 应激/UPR和肌肉疾病。我们将检验这一普遍假设，即偶联性肌病的相似性 不同偶联蛋白的突变是由高度合作的双向功能偶联引起的 在CaV1.1、CaMKII、RyR1和Casq1之间。我们的目标是：1.定义改变的CaV1.1功能状态的作用 偶联肌病中的转化和CaMKII激活。2.量化与对联疾病相关的影响 RyR1磷酸化突变及其对CaV1.1功能和Casq1的影响 保留在JSR。3.明确Casq1错位和内质网应激在复联肌病中的作用。我们会 也测试4PBA的能力，它可以缓解内质网应激，改善由以下原因引起的肌肉疾病的肌肉功能 偶联蛋白的突变。

The skeletal muscle L-type Ca2+ channel (CaV1.1) in the transverse tubules, the ryanodine receptor (RyR1) in the sarcoplasmic reticulum (SR), and calsequestrin (Casq1) in the lumen of junctional SR (jSR) are key components of a macromolecular complex termed the couplon which regulates excitation-contraction coupling (ECC). Mutations in RyR1, CaV1.1, and Casq1 underlie human myopathies with overlapping pathological features. With the exception of dantrolene for malignant hyperthermia, there are no FDA approved interventions for any of these myopathies. Mice with a mutations CaV1.1 (E1014K), RyR1 (I4895T) and Casq1 (D244G) develop myopathies that increase in severity with age and their muscles display Casq1 mislocalization and persistent ER stress. This application is designed to elucidate the mechanisms by which mutation-associated alterations in a CaMKII-dependent pathway lead to ER stress/UPR and muscle disease. We will test the general hypothesis that the similarities in couplon myopathies arising from mutations in different couplon proteins are due to highly cooperative, bidirectional functional coupling between CaV1.1, CaMKII, RyR1 and Casq1. Our aims are to: 1. Define the roles of altered CaV1.1 functional state transitions and CaMKII activation in couplon myopathies. 2. Quantify the effects of couplon disease-associated mutations on RyR1 phosphorylation and the phosphorylation-mediated effects on CaV1.1 function and Casq1 retention at the jSR. 3. Define the roles of Casq1 mislocalization and ER stress in the couplon myopathies. We will also test the ability of 4PBA, which alleviates ER stress, to improve muscle function in myopathies that arise from mutations in couplon proteins.