CELLULAR MAGNESIUM AND CALCIUM ION HOMEOSTASIS IN HEART

心脏细胞镁和钙离子稳态

• 批准号: 6564803
• 负责人: Antonio Scarpa
• 金额: $ 17.41万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564803
• 关键词: adenosine; antiport; calcium ion; cardiac myocytes; cyclic AMP; homeostasis; ion transport; laboratory rat; magnesium; magnesium ion; membrane transport proteins; mitochondrial membrane; myocardium; neuromuscular transmission; norepinephrine; protein kinase C; tissue /cell culture

Despite the abundance of Mg2+ in the body and within tissues in the body and within tissues, little is known about the regulation of cellular and plasma Mg2+ homeostasis. Studies conducted during the last nine years of finding to this Project, as well as those many other laboratories, have shown that cellular Mg2+ homeostasis is very active, has sophisticated and multiple forms of regulation and may provide, directly or indirectly, a novel role in regulating cell function and metabolism. Specific hormonal stimulation and changes in intracellular second messenger level induce the transport of large and rapid amounts of Mg2+ from heart into the extracellular milieu and ultimately into the bloodstream, or vice versa. This proposal continues to use a large variety of models (perfused hearts, myocytes, other isolated cells, permeabilized cells, isolated organelles, purified proteins) and experimental approaches (31P NMR, Electron Probe, Microanalysis, cell imaging, isotopic potentiometric techniques to acquire or integrate the knowledge on MG1+ homeostasis in heart. The objective of this application is o test several major hypothesis: That in myocytes there is a multiplicity of Mg2+ transporters mediating Mg2+ uptake and release, as well as a redundancy of signaling pathways activating and inhibiting Mg2+ transport. That cellular Mg2+ release may be a major part of the alpha1 or beta adrenergic response. That Mg2+ efflux from myocytes increases interstitial Mg2+ concentration in the myocardium and stimulates adenosine production. That in the heart a fraction of the large efflux of Mg2+ is coupled to Ca2+ uptake through a novel Mg2+-Ca2+ anti-porter Hence, Mg2+ efflux stimulated by catecholamines may be an additional pathway of Ca2+ entry. That the accumulation of Mg2+ in heart and other tissues is unaffected by extracellular Mg2+ but is independently regulated by specific signaling pathways through protein kinase C.

尽管体内和组织内含有丰富的 Mg2+，但人们对细胞和血浆 Mg2+ 稳态的调节知之甚少。该项目以及许多其他实验室在过去九年的研究中进行的研究表明，细胞 Mg2+ 稳态非常活跃，具有复杂且多种形式的调节，并且可能直接或间接地在以下方面发挥新作用：调节细胞功能和新陈代谢。特定的激素刺激和细胞内第二信使水平的变化诱导大量且快速的 Mg2+ 从心脏转运到细胞外环境并最终进入血液，反之亦然。该提案继续使用多种模型（灌注心脏、肌细胞、其他分离细胞、透化细胞、分离细胞器、纯化蛋白质）和实验方法（31P NMR、电子探针、微量分析、细胞成像、同位素电位技术来获取或整合有关心脏 MG1+ 稳态的知识 本应用的目的是测试几个主要假设： 在肌细胞中存在多种介导 Mg2+ 的 Mg2+ 转运蛋白。摄取和释放，以及激活和抑制 Mg2+ 转运的信号通路冗余，细胞 Mg2+ 释放可能是 α1 或 β 肾上腺素能反应的主要部分，心肌细胞的 Mg2+ 流出增加了心肌间质 Mg2+ 浓度并刺激腺苷。在心脏中，大量 Mg2+ 流出的一小部分通过一种新颖的方法与 Ca2+ 的吸收相结合。 Mg2+-Ca2+ 反转运蛋白 因此，儿茶酚胺刺激的 Mg2+ 外流可能是 Ca2+ 进入的另一条途径。 心脏和其他组织中 Mg2+ 的积累不受细胞外 Mg2+ 的影响，而是通过蛋白激酶 C 受到特定信号通路的独立调节。