Control Mechanisms of Cardiac Proteins and Enzymes

此申请是为了更新一个始于1986年的计划项目。拟议的研究是该计划在当前资助期内取得进展的产物，包括四个项目和两个支持核心，重点关注心脏糖苷敏感蛋白的结构/功能的中心主题。参与研究的研究人员具有膜生物化学、蛋白质化学、分子遗传学、细胞生物学和心脏生理学/药理学方面的专业知识，他们将联合收割机共同努力进行以下研究：第一个项目涉及位于细胞小窝微区的心脏Na+/K+-ATP酶池的离子泵和信号转导功能的表征 膜，心苷诱导的信号蛋白进出心脏小窝的交通，以及这种改变交通的功能后果。下一个项目提出研究人胃H+/K+-ATP酶的结构/功能关系和反应机制，该酶对强心苷敏感并参与离子稳态。还提出了一个新发现的肌肉特异性成员的β-亚基家族的P-ATP酶的功能特性的研究。下一个项目的研究旨在鉴定Na与其近邻之间形成的有组织的信号复合物，分子间结构域相互作用的性质，以及心脏糖苷诱导的这些相互作用的变化和由此产生的功能。最后一个项目提出的研究旨在表征的机制和途径，连接强心苷与Na ATP酶的相互作用，心脏线粒体KATP通道，以及这些途径对缺血性损伤的保护作用。拟议的研究预计将扩大知识的生物作用的心脏Na+/K+-ATP酶在以前未探索的方向，并提供新的信息的基础上，作为药物的强心苷的治疗价值，其假定的激素作用，可以进行评估。

This applicationis for the renewal of a program project that was initiated in 1986. The proposed research is the outgrowth of the program's progressd uring the current funding period,a nd consists of four projects and two supporting cores focused on the central theme of the structure/function of cardiac glycoside-sensitive proteins. The participating investigators with expertise in membrane biochemistry, protein chemistry, molecular genetics, cell biology,and cardiac physiology/pharmacology will combine their efforts to conduct the following studies: The first Project deals with the characterization of ion pumping and signal transducing functions of a pool of cardiac Na+/K+-ATPase that is localized in the caveolae microdomains of the cell membrane, the cardiacglycoside-induced traffic of signaling proteins into and out of cardiac caveolae, and the functional consequences of this altered traffic. The next Project proposes studies on the structure/function relationship and the reaction mechanism of a humann on-gastric H+/K+-ATPase that is sensitive to cardiac glycosides and is involved in ion homeostasis. Also proposed are studies on the functional characterization of a newly discovered muscle-specific member of the beta-subunit family of P-ATPases. Studies of the next Project are aimed at the identification of organized signaling complexes formed between Na and its close neighbors,the nature of the intermolecular domain interactions, and the cardiac glycoside-induced changes in these interactions and the resulting functions. The final Project proposes studies aimed at the characterization of the mechanisms and the pathways that link cardiac glycoside interaction with Na ATPase to the cardiac mitochondrial KATP channels, and the protective role of these pathways against ischemic damage. The proposed studies are expected to expand knowledge on the biological role of cardiac Na+/K+-ATPase in previously unexplored directions, and to provide new information on the basis of which the therapeutic value of cardiac glycosides as drugs, and their postulated hormonal roles, may be evaluated.