CALCIUM-DEPENDENT INACTIVATION OF SR CALCIUM RELEASE

钙依赖性 SR 钙释放失活

• 批准号: 3457115
• 负责人: BRUCE J SIMON
• 金额: $ 7.81万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3457115
• 关键词: Anura; calcium binding protein; calcium channel blockers; calcium metabolism; calcium transporting ATPase; calmodulin; computer simulation; heart cell; hormone inhibitor; hormone regulation /control mechanism; mathematical model; myofibrils; nucleotides; ruthenium; ryanodine; sarcoplasmic reticulum; secretion; striated muscles

The long-term objectives of my research are to characterize the properties of calcium release from the sarcoplasmic reticulum (SR) in skeletal muscle and determine the mechanism which links depolarization of the transverse tubular system to release of calcium from the SR during excitation. The specific aims of this project are to: i) demonstrate that inactivation of calcium release is calcium-dependent and determine if inactivation occurs in a restricted space at the release site; ii) develop and test a kinetic model for calcium-dependent inactivation; iii) determine the underlying molecular mechanism of inactivation; iv) study the effects of elevated (Ca2+) on charge movement and v) use this model of inactivation of SR calcium release in skeletal muscle to stimulate the properties of calcium release and uptake in other preparations. The rate of release of calcium will be calculated from (Ca2+) transients measured in single, cut skeletal muscle fibers from frog voltage clamped in a double Vaseline gap chamber. The indicator Antipyrylazo III will be used to measure changes in myoplasmic (Ca2+) from which the rate of calcium release will be calculated. The methodology will be developed to rapidly step the myoplasmic (Ca2+) using "caged calcium" and used in a variety of experiments to study the mechanism of inactivation. A preliminary model for calcium-dependent inactivation will be tested and the underlying mechanism of action explored by studying the effects of calmodulin and calmodulin inhibitors on the characteristics of inactivation. The inactivation model will be incorporated into a general model for calcium-induced calcium release. Simulations of calcium release and uptake in various preparations will be carried out and the effects of ruthenium red, (Mg2+), nucleotides, and ryanodine on release will be simulated. A model for calcium oscillations in cardiac cells will be developed and tested.

我研究的长期目标是表征 肌浆网 (SR) 释放钙的特性 在骨骼肌中并确定链接的机制 横向管状系统去极化以释放 激发期间来自 SR 的钙。 该项目的具体目标是： i) 证明 钙释放失活是钙依赖性的并决定 如果失活发生在释放地点的有限空间内； ii) 开发并测试钙依赖性动力学模型 失活； iii) 确定潜在的分子机制 失活； iv) 研究 (Ca2+) 升高对电荷的影响 运动和 v) 使用 SR 钙失活模型 在骨骼肌中释放以刺激钙的特性 其他制剂中的释放和吸收。 钙的释放率由 (Ca2+) 计算 在青蛙的单个、切割的骨骼肌纤维中测量瞬态 电压钳位在双凡士林间隙室中。 指标 Antipyrylazo III 将用于测量肌浆的变化 (Ca2+)，由此计算钙释放速率。 将开发该方法来快速步进肌质 (Ca2+)使用“笼钙”并用于各种实验 研究失活机制。 初步模型为 将测试钙依赖性失活和潜在的 通过研究钙调蛋白的作用探索作用机制 以及钙调蛋白抑制剂的失活特性。 失活模型将被纳入通用模型 用于钙诱导的钙释放。 钙的模拟 将进行各种制剂的释放和吸收， 钌红、(Mg2+)、核苷酸和兰尼碱的作用 发布时将进行模拟。 钙振荡模型 心脏细胞将被开发和测试。