Regulation of Mg2+ Homeostasis in Heart and Liver

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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.