Regulation of Mg2+ Homeostasis in Heart and Liver

描述（来自申请人的摘要的逐字）： Mg 2+在体内和组织内，对Mg 2+的调节知之甚少。 细胞和血浆Mg 2+稳态。在过去十年中进行的研究， 通过这个实验室和许多其他实验室，已经表明细胞Mg 2+稳态 非常活跃，具有复杂和多种形式的监管， 直接或间接地提供调节细胞功能的新作用， 新陈代谢.特异性激素刺激和细胞内秒数的变化 信使水平诱导大量和快速的Mg 2+从 许多组织进入细胞外环境，并最终进入 血液循环，反之亦然。在这种大量的细胞Mg 2+吸收过程中， 释放时，无细胞溶质（Mg 2+）保持基本恒定。因此， 合理假设Mg 2+不调节酶，通道或 胞浆结构域中的转运蛋白，但那些面向细胞外或 胞内结构域，其中Mg 2+浓度迅速变化。 该提案将使用各种各样的模型（灌注心脏和肝脏， 肌细胞、肝细胞、透化细胞、分离的细胞器、纯化的 蛋白质）和实验方法（31 P NMR，电子探针微量分析， 细胞成像、同位素、电位测定技术）来获取或整合 了解镁离子在心脏和肝脏中的动态平衡。 本申请的目的是测试几个主要假设： 在心肌细胞和肝细胞中，存在多种Mg 2+转运蛋白介导 Mg 2+摄取和释放，以及信号传导途径的冗余 激活和抑制Mg 2+转运;细胞Mg 2+释放可能是 整合的α 1或β肾上腺素能反应的主要部分; 心脏和肝脏中大量流出的Mg 2+的一部分与Ca 2+偶联 通过新型Mg 2 +-Ca 2+反向转运蛋白摄取。因此，Mg 2+外排刺激 儿茶酚胺可能是Ca 2+进入的另一途径; Mg 2+流出 增加心肌间质中Mg 2+浓度， 影响质膜水平的许多反应，其中之一， 腺苷生产的间隙空间，将被研究;和， Mg 2+在心脏和肝脏中的积累不受细胞外Mg 2+的影响， 是由特定的信号通路独立调节的， 特异性蛋白激酶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.