Regulation of Mg2+ Homeostasis in Heart and Liver

心脏和肝脏中 Mg2 稳态的调节

• 批准号: 6325433
• 负责人: Antonio Scarpa
• 金额: $ 34.43万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6325433
• 关键词: adrenergic receptor; antiport; calcium flux; cardiac myocytes; catecholamines; electrolyte balance; electron probe spectrometry; enzyme activity; heart metabolism; laboratory rat; liver cells; liver metabolism; magnesium ion; membrane transport proteins; nuclear magnetic resonance spectroscopy; potentiometry; protein kinase C

DESCRIPTION (Verbatim from the Applicant's Abstract): Despite the abundance of Mg2+ in the body and within tissues, little is known about the regulation of cellular and plasma Mg2+ homeostasis. Studies conducted during the last decade, by this and 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 many tissues into the extra-cellular milieu and ultimately into the bloodstream, or vice versa. During this massive cellular Mg2+ uptake and release, the cytosolic-free (Mg2+) remains essentially constant. Hence, it is reasonable to postulate that Mg2+ does not regulate enzymes, channels or transporters in the cystosolic domain, but those facing extracellular or intravesicular domains where Mg2+ concentration changes rapidly. This proposal will use a large variety of models (perfused hearts and liver, myocytes, hepatocytes, permeabilized cells, isolated organelles, purified proteins) and experimental approaches (31P NMR, Electron Probe Microanalysis, cell imaging, isotopes, potentiometric techniques) to acquire or integrate the knowledge on Mg2+ homeostasis in heart and livers. The objective of this application is to test several major hypotheses: that in myocytes and hepatocytes there is a multiplicity of Mg2+ transporters mediating Mg2+ uptake and release, as well as a redundancy of signalling pathways activating and inhibiting Mg2+ transport; that cellular Mg2+ release may be a major part of the integrated alpha1 or beta adrenergic response; that in the heart and liver a fraction of the large efflux of Mg2+ is coupled to Ca2+ uptake through a novel Mg2+-Ca2+ antiporter. Hence, Mg2+ efflux stimulated by catecholamines may be an additional pathway of Ca2+ entry; that Mg2+ efflux from myocytes increases interstitial Mg2+ concentration in the myocardium, thus affecting many responses at the level of the plasma membrane, one of which, adenosine production in the interstitial space, will be studied; and that the accumulation of Mg2+ in heart and liver is unaffected by extracellular Mg2+ but is independently regulated by specific signalling pathways involving activation of specific protein kinase C.

描述（逐字化申请人的摘要）：尽管有很多 MG2+在体内和组织中，对调节的调节知之甚少 细胞和血浆MG2+稳态。在过去十年中进行的研究 通过此和许多其他实验室，已经表明细胞MG2+稳态 非常活跃，具有复杂和多种形式的监管，可能 直接或间接地提供调节细胞功能的新作用， 代谢。特定的激素刺激和细胞内第二 使者级别诱导大量和快速的MG2+从 许多组织进入细胞外环境，并最终进入 血液，反之亦然。在这种庞大的细胞MG2+摄取和 释放，无胞质（MG2+）基本上保持恒定。因此，是 合理地假设MG2+不调节酶，通道或 囊肿域中的转运蛋白，但面对细胞外或 MG2+浓度迅速变化的内内结构域。 该建议将使用多种模型（灌注心脏和肝脏， 心肌细胞，肝细胞，透化细胞，孤立的细胞器，纯化 蛋白质）和实验方法（31p NMR，电子探针微分析， 细胞成像，同位素，电位测量技术）以获取或整合 关于心脏和肝脏中MG2+稳态的知识。 该应用的目的是检验几个主要假设： 肌细胞和肝细胞有多种介导的MG2+转运蛋白 MG2+摄取和释放，以及信号通路的冗余 激活和抑制MG2+转运；该细胞MG2+释放可能是 综合α1或β肾上腺素能反应的主要部分；那在 心脏和肝脏的一小部分Mg2+的大外分耦合到Ca2+ 通过新型的MG2+ -CA2+抗焦点吸收。因此，MG2+外排被刺激 儿茶酚胺可能是Ca2+进入的额外途径；那个MG2+外排 从心肌细胞增加了心肌中的间质Mg2+浓度，因此 影响质膜水平上的许多反应，其中之一 将研究中间空间中的腺苷产生；那是 心脏和肝脏中MG2+的积累不受细胞外Mg2+的影响，但 由涉及激活的特定信号通路独立调节 特异性蛋白激酶C.