Ca signaling cross-talk from SR to mitochondria in heart muscle

Ca 信号从 SR 到心肌线粒体的串扰

基本信息

批准号：
10265413
负责人：
Pei-Hui Lin
金额：
$ 64.75万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265413
关键词：
Ablation Acute Affect Architecture Arrhythmia Cardiac Cardiac Myocytes Cardiovascular Diseases Cations Cells Complementary DNA Coupling Crystallization Cultured Cells Defect Disease Electron Microscopy Endoplasmic Reticulum Epithelial Cells Functional disorder Genes Genetic Health Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Human Human Genome Hypertension Ion Channel Ions Isoproterenol Knock-out Link Mediating Membrane Mitochondria Movement Mus Muscle Cells Mutagenesis Mutation Myocardial dysfunction Myocardium Names Neonatal Operative Surgical Procedures Osteogenesis Imperfecta Pathologic Pathology Patients Peptides Permeability Phase Physiological Physiology Protein Isoforms Proteins RNA Interference Regulation Research Role RyR2 Ryanodine Receptor Calcium Release Channel Sarcoplasmic Reticulum Signal Transduction Skeletal Muscle Smooth Muscle Stress Structure System Tail Testing Tissues Toxic effect Transgenic Organisms airway epithelium biological adaptation to stress cardiogenesis cell type constriction coronary fibrosis design experimental study heart function in vivo mRNA Differential Displays mitochondrial dysfunction mouse genome mutant novel pup receptor reconstitution respiratory synthetic peptide

项目摘要

Project Summary Mitochondria and sarcoplasmic reticulum (SR) form close interfaces in cardiomyocytes where the propagation of Ca signals from SR to mitochondria contributes to heart function under physiologic and pathologic conditions. TRIC is a novel class of trimeric intracellular cation channels located at the SR or endoplasmic reticulum (ER) of multiple cell types, which function as counter-ion channels that allow flow of K ions into the SR/ER during the acute phase of Ca release. Genetic ablations or mutations of TRIC channels are associated with hypertension, heart disease, respiratory defects and brittle bone disease. The recent crystal structure of TRIC proteins confirms the homotrimeric architecture of a cation channel. Within the human and mouse genomes, there are two TRIC isoforms, TRIC-A and TRIC-B, that display differential functions in regulation of Ca signaling in excitable and non-excitable cells. While our past research efforts primarily focused on understanding the physiological function for TRIC-A in skeletal and smooth muscle and to a lesser extent the role of TRIC-B in epithelial cells, the role of TRIC in cardiac physiology and disease remains largely unexplored. Here we present evidence that TRIC-A, in addition to modulation of the SR permeability to K ions, functions as an integral component of the physiological control mechanism of Ca signaling in cardiac muscle. We found that the carboxyl-tail domain of TRIC-A interacts with the RyR2 channel to directly modulate Ca release from the SR. The TRIC-A-/- mice develop arrhythmia, severe cardiac hypertrophy and fibrosis following isoproterenol treatment or transverse aortic constriction (TAC) surgery. Isolated TRIC-A-/- cardiomtocytes display mitochondria dysfunction that likely reflects SR Ca overload-induced mitochondria toxicity under stress conditions. As uncontrolled Ca release has been implicated in mitochondrial dysfunction in cardiac pathology, we hypothesize that “TRIC interaction with RyR2 modulates SR Ca release and crosstalk with mitochondria. Absence of TRIC leads to Ca overload inside SR and causes stress-induced Ca toxicity to mitochondria. The dysregulated SR-mitochondria crosstalk contributes to the development of heart failure”. We further propose that targeting TRIC- mediated SR-mitochondria crosstalk represents a novel means for treatment of cardiovascular diseases. Our experiments designed in this project contain two specific aims: Aim 1 - to define the functional interaction between TRIC-A/B and RyR2 in regulating the cross-talk of Ca signaling from SR to mitochondria in cardiomyocytes under physiologic and pathologic conditions; and Aim 2 - to elucidate the in vivo role of TRIC-A in mediating stress-induced changes in heart function.

项目概要线粒体和肌浆网 (SR) 在心肌细胞中形成紧密的界面，其中 Ca 信号从 SR 传播到线粒体有助于生理和心理条件下的心脏功能 TRIC 是一类位于 SR 的新型三聚体细胞内阳离子通道。或多种细胞类型的内质网（ER），其功能作为反离子通道，允许在 Ca 释放的急性期，K 离子流入 SR/ER。 TRIC 通道与高血压、心脏病、呼吸系统缺陷和骨质疏松有关 TRIC 蛋白的最新晶体结构证实了同源三聚体结构。在人类和小鼠基因组中，有两种 TRIC 亚型：TRIC-A 和 TRIC-A。 TRIC-B，在兴奋性和非兴奋性 Ca 信号传导调节中表现出不同的功能而我们过去的研究工作主要集中在了解细胞的生理功能。 TRIC-A 在骨骼肌和平滑肌中的作用，以及 TRIC-B 在上皮细胞中的较小程度的作用， TRIC 在心脏生理学和疾病中的作用在很大程度上仍未被探索，在此我们提供证据。 TRIC-A 除了调节 K 离子的 SR 渗透性之外，还起到积分作用我们发现心肌中 Ca 信号传导的生理控制机制的组成部分。 TRIC-A 的羧基尾结构域与 RyR2 通道相互作用，直接调节 Ca2+ 的释放 SR. TRIC-A-/- 小鼠出现心律失常、严重心脏肥大和纤维化。异丙肾上腺素治疗或横主动脉缩窄 (TAC) 手术。心肌细胞表现出线粒体功能障碍，这可能反映了 SR Ca 超载引起的应激条件下的线粒体毒性与不受控制的 Ca 释放有关。心脏病理学中的线粒体功能障碍，我们捕获了“TRIC 与 RyR2 的相互作用” 调节 SR Ca 释放以及与线粒体的串扰。 TRIC 的缺失会导致 Ca 超载。 SR 内部并导致应激诱导的 Ca 对线粒体的毒性。串扰会导致心力衰竭的发生”，我们进一步建议针对 TRIC-。介导的 SR-线粒体串扰代表了治疗心血管疾病的新方法我们在该项目中设计的实验包含两个具体目标：目标 1 - 定义疾病。 TRIC-A/B 和 RyR2 之间的功能相互作用在调节 SR Ca 信号传导的串扰中生理和病理条件下心肌细胞中的线粒体；以及目标 2 - 阐明 TRIC-A 在介导应激引起的心脏功能变化中的体内作用。