Redox Control of Sarcoplasmic Reticulum Calcium Release

肌浆网钙释放的氧化还原控制

• 批准号: 6522151
• 负责人: JONATHAN J ABRAMSON
• 金额: $ 33.74万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-20 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522151
• 关键词: NAD(P)H dehydrogenase; SDS polyacrylamide gel electrophoresis; biological signal transduction; calcium channel; calcium channel blockers; chemical kinetics; enzyme activity; homeostasis; ion transport; ischemia; laboratory rabbit; laboratory rat; lipid bilayer membrane; muscle strength; myocardium; oxidation reduction reaction; oxidative stress; perfusion; protein structure function; receptor binding; receptor expression; sarcoplasmic reticulum; striated muscles; swine; thiols

DESCRIPTION (provided by applicant): Both skeletal and cardiac muscle sarcoplasmic reticulum (SR) are sensitive to oxidative stress induced directly by free radicals, and indirectly by an increase in the cellular redox potential. Oxidative stress results from cardiac ischemia and reperfusion, and in skeletal muscle results in muscle fatigue. The molecular mechanism by which the SR controls and responds to changes in its redox environment, and how this influences Ca2+ homeostasis is the main goal of this research proposal.The major site of oxidative damage to SR appears to be highly reactive sulfhydryl groups, which under mildly oxidative conditions, oxidize to disulfides. This causes the Ca2+ release channel from SR to open and the intracellular Ca2+ concentration to increase. It is our goal to measure the redox potential of these thiols in both cardiac and skeletal muscle, and to determine how physiologically relevant components in the cellular environment control the redox potential of the ryanodine receptor. Using single channel measurements, we will also determine how the Ca2+ release channel responds to alterations in the redox potential on both its cytoplasmic and lumenal sides of the SR membrane. Moreover, rapid changes in the local redox potential will enable us to determine how quickly the receptor responds to changes in its redox environment.Not only does this proposal focus on how the ryanodine receptor responds to its redox environment, but it also identifies for the first time an endogenous NAD (P) H dependent oxidase from SR, which produces superoxide, and which stimulates the ryanodine receptor. It is our goal to characterize this oxidase, to understand how its activity is influenced by changes that occur to the muscle during increased activity, and to determine its role in skeletal muscle fatigue.

描述（由申请方提供）：骨骼肌和心肌肌浆网（SR）对自由基直接诱导的氧化应激和细胞氧化还原电位增加间接诱导的氧化应激敏感。心肌缺血和再灌注导致氧化应激，骨骼肌中的氧化应激导致肌肉疲劳。SR控制和响应其氧化还原环境变化的分子机制，以及这如何影响Ca2+稳态是本研究的主要目标proposal.The主要网站的氧化损伤SR似乎是高活性巯基，在温和的氧化条件下，氧化二硫化物。这导致SR的Ca 2+释放通道打开，细胞内Ca 2+浓度增加。 我们的目标是测量这些硫醇在心肌和骨骼肌中的氧化还原电位，并确定细胞环境中的生理相关成分如何控制兰尼碱受体的氧化还原电位。使用单通道测量，我们还将确定如何Ca2+释放通道响应于其细胞质和内腔侧的SR膜的氧化还原电位的改变。此外，在当地的氧化还原电位的快速变化将使我们能够确定如何快速的受体响应于其氧化还原环境的变化，不仅关注这一建议的ryanodine受体如何响应其氧化还原环境，但它也确定了第一次从SR的内源性NAD（P）H依赖氧化酶，产生超氧化物，并刺激ryanodine受体。我们的目标是表征这种氧化酶，了解其活性如何受到活动增加期间肌肉发生的变化的影响，并确定其在骨骼肌疲劳中的作用。