CELLULAR MAGNESIUM AND CALCIUM ION HOMEOSTASIS IN HEART

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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.