Magnesium, the second most abundant cellular cation after potassium, is essential to regulate numerous cellular functions and enzymes, including ion channels, metabolic cycles, and signaling pathways, as attested by more than 1000 entries in the literature. Despite significant recent progress, however, our understanding of how cells regulate Mg2+ homeostasis and transport still remains incomplete. For example, the occurrence of major fluxes of Mg2+ in either direction across the plasma membrane of mammalian cells following metabolic or hormonal stimuli has been extensively documented. Yet, the mechanisms ultimately responsible for magnesium extrusion across the cell membrane have not been cloned. Even less is known about the regulation in cellular organelles. The present review is aimed at providing the reader with a comprehensive and up-to-date understanding of the mechanisms enacted by eukaryotic cells to regulate cellular Mg2+ homeostasis and how these mechanisms are altered under specific pathological conditions.

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MgSO4 exposure before preterm birth is neuroprotective, reducing the risk of cerebral palsy and major motor dysfunction. Neonatal inflammatory cytokine levels correlate with neurologic outcome, leading us to assess the effect of MgSO4 on cytokine production in humans. We found reduced maternal TNF-α and IL-6 production following in vivo MgSO4 treatment. Short-term exposure to a clinically effective MgSO4 concentration in vitro substantially reduced the frequency of neonatal monocytes producing TNF-α and IL-6 under constitutive and TLR-stimulated conditions, decreasing cytokine gene and protein expression, without influencing cell viability or phagocytic function. In summary, MgSO4 reduced cytokine production in intrapartum women, term and preterm neonates, demonstrating effectiveness in those at risk for inflammation-associated adverse perinatal outcomes. By probing the mechanism of decreased cytokine production, we found that the immunomodulatory effect was mediated by magnesium and not the sulfate moiety, and it was reversible. Cellular magnesium content increased rapidly upon MgSO4 exposure, and reduced cytokine production occurred following stimulation with different TLR ligands as well as when magnesium was added after TLR stimulation, strongly suggesting that magnesium acts intracellularly. Magnesium increased basal IκBα levels, and upon TLR stimulation was associated with reduced NF-κB activation and nuclear localization. These findings establish a new paradigm for innate immunoregulation, whereby magnesium plays a critical regulatory role in NF-κB activation, cytokine production, and disease pathogenesis.

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Magnesium is abundant in the mammalian body and the second most abundant cation in cells. Because the concentration of intracellular free Mg2+ is relatively high (0.2-1 mM), Mg2+ is unlikely to act as a second messenger, like Ca2+, by rapidly changing its cytosolic concentration. But changes in Mg2+ do have profound effects on cellular metabolism, structure and bioenergetics. Key enzymes or metabolic pathways, mitochondrial ion transport, Ca2+ channel activities in the plasma membrane and intracellular organelles, ATP-requiring reactions, and structural properties of cells and nucleic acids are modified by changes in Mg2+ concentration. Yet, although some information is available from giant cells and bacteria, little is known about the regulation of intracellular Mg2+ in mammalian cells. Here we report a new transport mechanism for Mg2+ across the sarcolemma of cardiac cells in both intact hearts and dissociated myocytes. We show that noradrenaline, through beta-adrenergic stimulation and increase of cyclic AMP, stimulates a large efflux of Mg2+ from cardiac cells. This transport is of major dimensions and can move up to 20% of total cellular Mg2+ within a few minutes.

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The abundance of magnesium (Mg 2+ ) within mammalian cells is consistent with its relevant role in regulating tissue and cell functions. At the last count, more than three hundred and fifty enzymes, aside from metabolic cycles, appear to require and be regulated by concentrations of Mg 2+ that are well within the physiological range observed in tissues and cells. The absence of detectable major changes in cellular free [Mg 2+ ], and the extremely slow turn-over of the cation across the cell plasma membrane under quiescent condition has supported for more than three decades the assumption that cellular Mg 2+ content is kept constant at the level necessary for enzyme and channel function, and that its concentration does not require drastic and rapid changes to form complex with ATP and other phosphonucleotides.In the last decade, a large body of new experimental observations has significantly reverted this way of thinking.Compelling evidence now suggests that large fluxes of Mg 2+ can cross the cell plasma membrane in either direction following a variety of hormonal and non-hormonal stimuli, resulting in major changes in total and, to a lesser extent, free Mg 2+ content within tissues, and in a marked variation in the opposite direction of circulating Mg 2+ level. The present review will attempt to update our knowledge in this area and provide some insights on how changes in cellular Mg 2+ content can result in a modification of the activity rate for several cellular enzymes. Mg 2+ AS AN INTRACELLULAR MESSENGERFor many decades the role of Mg 2+ in biological systems has been hampered by the difficulty of measuring accurately and selectively Mg 2+ in cell and biological system. This has been partly ameliorated by the introduction of atomic absorbance spectrophotometry in the early 1950s and, more recently, by additional analytical methods. Mg2+ is now recognized being indispensable for enzyme activity and structural modification of phosphometabolites or channels.Yet, the general consensus from a large body of evidence indicates that Mg 2+ concentration is relatively stable within the cell and that whilst Mg 2+ presence is necessary for cell function, it will not modulate -like Ca 2+ -cell function by changing concentrations within the cytsosol.In fact, studies attempting to equate Ca 2+ and Mg 2+ as signaling molecules for cytosolic enzymes have been disappointing. Ca 2+ is a signaling molecule because of the following conditions: a) the free cytosolic concentration is extremely low; b) the concentrations in plasma and cytosolic reservoirs are very high, establishing a large concentration gradient across biological membranes; c) because of the low resting Ca CHANGES IN SERUM MG 2+ LEVELCirculating Mg 2+ level is 1.5-1.7 mEq/L in humans and in many mammals (1-3). A decrease in serum Mg 2+ level has been reported to occur during several chronic diseases, both in humans and in animals (4-6). Yet, there is a remarkable lack of information, or contrasting result, as to whether magnesemia undergoes c...

The acute administration of ethanol mobilizes a considerable amount of Mg2+ from perfused rat livers and isolated hepatocytes in a dose-dependent fashion in the absence of release of cellular K+ or lactate dehydrogenase (LDH) in the extracellular medium. Mg2+extrusion becomes detectable within 2 min and reaches the maximum within 8 min after ethanol addition, declining toward the basal value thereafter irrespective of the persistence of alcohol in the perfusion system and the dose of ethanol administered. The effect is the result of a specific impairment of Mg2+transport and/or regulatory mechanisms. In fact, Mg2+ extrusion does not occur under conditions in which 1) ethanol is replaced by an equivalent dose of DMSO, 2) amiloride or imipramine are used as inhibitors of the Na+/Mg2+exchanger, 3) extracellular Na+ is replaced by an equimolar concentration of choline chloride, and 4) 4-methylpyrazole is used to specifically inhibit alcohol dehydrogenase and cytochrome P-4502E1. Finally, the observation that the cellular level of ATP is markedly reduced after acute ethanol administration would suggest that Mg2+ extrusion results from a decreased buffering capacity of cytosolic Mg-ATP complex.