C PROTEIN AND CROSS BRIDGE FUNCTION IN HEART MUSCLE

C 蛋白和心肌的跨桥功能

• 批准号: 2437668
• 负责人: SAUL WINEGRAD
• 金额: $ 31.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2437668
• 关键词: X ray crystallography; adenosine triphosphate; bioenergetics; crosslink; electron microscopy; heart contraction; laboratory rat; muscle proteins; myocardium; myofibrils; myosin light chain kinase; phosphorylation; protein kinase A; protein kinase C; protein structure function; radiotracer; second messengers; troponin

DESCRIPTION: (Adapted from the Investigator's Abstract) The duration of the contraction, the velocity of shortening, the rate of hydrolysis of ATP and the efficiency of the conversion of chemical to hydrodynamic energy can each be varied as the heart meets the requirements of the organism without jeopardizing its own viability. Modulation of contraction can occur from changes in Ca cycling or myofilament structure. Although almost every transmitter-based physiological mechanism for altering cardiac contractility is accompanied by phosphorylation of C protein and in several cases the regulatory light chain of myosin (LC2), little is known about the effects of these phosphorylations, singly or in combination, on contraction. Preliminary data indicate that phosphorylation of C protein is important in the modification of the kinetics of cross bridge cycling and the regulation of the efficiency of contraction. The goals of this proposal are to study: 1) the effects of phosphorylation of C protein alone and in combination with phosphorylation of LC2 on the contraction of the cardiac myocytes, in particular their efficiency; and 2) the relation of the changes in contraction to detectable changes in cross bridge structure. Three hypotheses will be evaluated: 1) Phosphorylation of C protein by PKA increases the rate of cross bridge cycling and decreases the efficiency of contraction; 2) Phosphorylation of LC2 with phosphorylation of C protein by PKC decreases the rate of cross bridge cycling and increases the efficiency of contraction; 3) The changes in cross bridge structure produced by the phosphorylations are consistent with the changes in the kinetics of cross bridge cycling. Relationships between contractile force, work, velocity, stiffness, ATP hydrolysis, efficiency and the phosphorylation of myofilament proteins and structure of cross bridges will be determined. The last will be examined in isolated thick filaments by electron microscopy and optical diffraction, and in skinned and intact fibers by x ray diffraction. Knowledge of the physiological mechanisms that modulate the economy and the efficiency of contraction is important for the management of disparities between the rate of energy supplied and the work done by the heart. By elucidating the relation among changes in energy use, phosphorylation of C protein and cross bridge structure in response to second messenger systems operating through protein kinases A and C, these studies will provide the basis for new pharmacological management of myocardial ischemia in both early and later stages.

描述：（根据调查人员的摘要进行了改编） 收缩，缩短速度，ATP的水解速率和 化学转化为流体动能的效率可以 随着心脏符合生物体的要求而变化 危害自己的生存能力。 收缩的调节可能会发生 CA循环或肌丝结构的变化。 虽然几乎每个 基于发射机的生理机制改变心脏收缩率 伴随C蛋白的磷酸化，在某些情况下 肌球蛋白的调节轻链（LC2），对 这些磷酸化，单独或合并，收缩。 初步数据表明，C蛋白的磷酸化在 跨桥骑行动力学和调节的动力学的修饰 收缩效率。 该建议的目标是研究： 1）单独使用C蛋白磷酸化并与 LC2对心肌细胞收缩的磷酸化，在 特别是他们的效率； 2）变化的关系 跨桥结构可检测到的变化的收缩。 三 将评估假设：1）PKA对C蛋白的磷酸化 提高越野骑自行车的速度并降低 收缩； 2）LC2磷酸化，通过C蛋白磷酸化 PKC降低了跨桥循环的速率并提高了效率 收缩； 3）由 磷酸化与交叉动力学的变化一致 桥骑自行车。 收缩力，工作，速度之间的关系， 刚度，ATP水解，效率和肌丝的磷酸化 将确定蛋白质和跨桥的结构。 最后的意愿 通过电子显微镜和光学检查在孤立的厚细丝中检查 衍射，以及X射线衍射中的皮肤和完整纤维。 了解调节经济和的生理机制 收缩效率对于管理差异很重要 在提供的能量速度和心脏所做的工作之间。 经过 阐明能源使用变化之间的关系，C的磷酸化 蛋白质和跨桥结构，以响应第二会使系统 通过蛋白激酶A和C进行操作，这些研究将提供 两者中心肌缺血的新药理管理的基础 早期和晚期。