Ryanodine Receptor Channels in Heart Failure

心力衰竭中的 Ryanodine 受体通道

• 批准号: 6999314
• 负责人: Sandor Gyorke
• 金额: $ 36.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999314
• 关键词: biological signal transduction; calcium channel; calcium flux; cardiac myocytes; heart failure; laboratory mouse; laboratory rabbit; laboratory rat; phosphorylation; receptor expression; ryanodine; sarcoplasmic reticulum

DESCRIPTION (provided by applicant): Abnormal handling of intracellular Ca has been identified as a major cause of heart failure (HF), a leading cause of death in the US. Despite intense effort, the precise mechanisms underlying the HF-related alterations of Ca signaling remain poorly understood. The overall goal of this proposal is to define the role of alterations of the sarcoplasmic reticulum (SR) Ca release channel/ryanodine receptor (RyR) in HF. In cardiac muscle, RyRs are activated by cytosolic Ca via the mechanism of Ca-induced Ca release (CICR). Data obtained recently in our laboratory shows that in addition to cytosolic Ca, RyRs are also controlled by Ca inside the SR at luminal sites. The presence of a luminal Ca sensor regulating release of SR Ca has profound implications for our understanding of intracellular Ca signaling in normal and diseased myocardium. For example, by linking the functional activity of RyR channels to the loading state of SR, the luminal Ca sensor stabilizes Ca release in the face of alterations of RyRs. Consequently, any factors affecting the properties of RyRs are compensated by changes in SR Ca load and concomitant luminal Ca-dependent changes in RyR channel activity. Our preliminary data suggest that this feedback mechanism might be compromised in HF, potentially leading to chronic depression of SR Ca release function. In the present proposal we will address the following questions: 1) Are the intrinsic gating properties of RyRs (i.e. regulation by cytosolic and luminal Ca) altered in HF? 2) What are the precise molecular mechanisms of these alterations? And 3) How do the proposed changes in RyRs contribute to abnormal Ca cycling in HF? To this end, single channel approaches in a reconstitution system and fluorescent calcium imaging techniques in isolated ventricular myocytes and whole beating hearts will be utilized to determine relationships between RyR properties and HF at multiple levels, using several well-established animal models of HF. The results of this study will improve our understanding of the mechanisms and role of altered Ca handling in HF.

描述（由申请人提供）：细胞内CA的异常处理已被确定为心力衰竭的主要原因（HF），这是美国的主要死亡原因。尽管进行了激烈的努力，但与HF相关的CA信号变化的确切机制仍然很少理解。该提案的总体目标是确定HF中肌质网（SR）CA释放通道/ryanodine受体（RYR）改变的作用。在心脏肌肉中，RYRS通过CA诱导的Ca释放（CICR）的机制被胞质CA激活。最近在我们的实验室中获得的数据表明，除了胞质CA外，RYRS还由SR内部的CA控制在腔位点。调节SR CA的腔内CA传感器的存在对我们对正常和患病心肌中细胞内CA信号传导的理解具有深远的影响。例如，通过将RYR通道的功能活性与SR的负载状态联系起来，腔CA传感器在RYRS的改变时稳定CA释放。因此，任何影响RYRS性质的因素都通过SR CA负载的变化和RYR通道活性的腔内CA依赖性变化来弥补。我们的初步数据表明，这种反馈机制可能在HF中受到损害，可能导致SR CA释放功能的慢性抑郁。在本提案中，我们将解决以下问题：1）HF在HF中改变了RYRS的内在门控特性（即对胞质和腔内CA的调节）？ 2）这些改变的精确分子机制是什么？ 3）RYRS的提议变化如何导致HF中的CA循环异常？为此，将利用几种良好的HF动物模型，在多个层次上，将利用单个通道方法和孤立心室肌细胞和整个跳动心脏中的单个通道方法和整个跳动的心脏中的荧光钙成像技术。这项研究的结果将提高我们对HF中CA处理改变的机制和作用的理解。