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（逐字摘自申请人的摘要）：尽管有大量的 Mg2+在体内和组织内的调节作用知之甚少 细胞和血浆 Mg2+ 稳态。过去十年进行的研究， 该实验室和许多其他实验室的研究表明，细胞 Mg2+ 稳态 非常活跃，具有复杂且多种形式的监管，并且可能 直接或间接地在调节细胞功能和 代谢。特定的激素刺激和细胞内第二个的变化 信使水平诱导大量且快速的 Mg2+ 转运 许多组织进入细胞外环境并最终进入 血液，反之亦然。在细胞大量吸收 Mg2+ 的过程中 释放后，游离的细胞质 (Mg2+) 保持基本恒定。因此，它是 合理地假设 Mg2+ 不调节酶、通道或 转运蛋白位于胞质结构域，但那些面向细胞外或 Mg2+浓度快速变化的囊泡内区域。 该提案将使用多种模型（灌注心脏和肝脏， 肌细胞、肝细胞、透化细胞、分离的细胞器、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 关于心脏和肝脏中 Mg2+ 稳态的知识。 此应用程序的目的是测试几个主要假设： 肌细胞和肝细胞中存在多种 Mg2+ 转运蛋白介导 Mg2+ 的吸收和释放，以及信号通路的冗余 激活和抑制 Mg2+ 转运；细胞内 Mg2+ 的释放可能是 综合 α1 或 β 肾上腺素能反应的主要部分；那个在 心脏和肝脏 大量流出的 Mg2+ 的一小部分与 Ca2+ 耦合 通过新型 Mg2+-Ca2+ 反向转运蛋白进行摄取。因此，Mg2+ 外流刺激 儿茶酚胺可能是 Ca2+ 进入的另一个途径； Mg2+流出 来自心肌细胞的 Mg2+ 增加了心肌间质的 Mg2+ 浓度，因此 影响质膜水平的许多反应，其中之一， 将研究细胞间隙中腺苷的产生；并且那 心脏和肝脏中 Mg2+ 的积累不受细胞外 Mg2+ 的影响，但 受涉及激活的特定信号通路独立调节 特定蛋白激酶 C.