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Structure and Function of the Cardiac Na+-Ca2+ Exchanger

心脏 Na -Ca2 交换器的结构和功能

基本信息

批准号：
8033710
负责人：
KENNETH PHILIPSON
金额：
$ 56.06万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-04-01 至 2012-09-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The plasma membrane (sarcolemma) of cardiac myocytes has high levels of Na+-Ca2+ exchange activity. Na+- Ca2+ exchange is an important regulator of intracellular Ca2+ and thus a major determinant of myocardial contractility. Na+-Ca2+ exchange is upregulated and may take on added significance during hypertrophy and heart failure. It is important to investigate the structure and molecular properties of the cardiac Na+-Ca2+ exchange molecule to gain understanding of the role of the exchanger in physiology and pathophysiology. Towards this goal, the specific aims of the proposal are as follows: 1. Structure and Regulation. The Na+-Ca2+ exchanger is regulated by nontransported intracellular Ca2+. The structure of the Ca2+ regulatory site has recently been determined. The goals are twofold: a. Determine the structures of other segments of the intracellular loop of the Na+-Ca2+ exchanger. b. Apply structural information to understand Ca2+ regulation at the molecular level. 2. Helix Packing, Dimerization, and Transport Pathway. The aim is to further investigate the packing arrangement of transmembrane segments within the Na+-Ca2+ exchanger and between exchanger dimers. Mutational approaches will be used to understand the ion translocation mechanism and pathway. 3. Application of Fluorescent Resonance Energy Transfer (FRET) to Study the Na+-Ca2+ Exchanger. The aim is to apply FRET to investigate conformational changes of the exchanger in vitro, in cells, and in a living organism. FRET will also be applied to investigate dimerization of the exchanger. The underlying hypothesis is that increased knowledge of the structure, function, and regulation of the Na+- Ca2+ exchanger molecule will directly lead to a better understanding of the role of the exchanger in physiological and pathophysiological settings. The increased knowledge will perhaps have pharmacological and clinical applications.

描述（申请人提供）：心肌细胞的质膜（肌膜）具有高水平的Na+-Ca2+交换活性。 Na+-Ca2+交换是细胞内Ca2+的重要调节剂，因此是心肌收缩力的主要决定因素。 Na+-Ca2+ 交换上调，并且在肥厚和心力衰竭期间可能具有额外的重要性。研究心脏Na+-Ca2+交换分子的结构和分子特性对于了解交换器在生理学和病理生理学中的作用非常重要。为实现这一目标，该提案的具体目标如下： 1. 结构和监管。 Na+-Ca2+ 交换器受非转运细胞内 Ca2+ 调节。 Ca2+ 调节位点的结构最近已确定。目标有两个：确定 Na+-Ca2+ 交换器细胞内环的其他部分的结构。 b.应用结构信息来了解分子水平上的 Ca2+ 调节。 2. 螺旋堆积、二聚化和运输途径。目的是进一步研究 Na+-Ca2+ 交换器内和交换器二聚体之间跨膜片段的堆积排列。突变方法将用于了解离子易位机制和途径。 3. 应用荧光共振能量转移（FRET）研究Na+-Ca2+交换剂。目的是应用 FRET 来研究体外、细胞和活体中交换器的构象变化。 FRET 还将用于研究交换剂的二聚化。基本假设是，增加对 Na+-Ca2+ 交换分子的结构、功能和调节的了解将直接导致更好地理解交换器在生理和病理生理环境中的作用。增加的知识也许会有药理学和临床应用。