Regulation of magnesium homeostasis and transport in mammalian cells
Mammalian cells tightly control cellular magnesium content by partitioning Mg2+ within cellular compartments and by transporting it across the plasma membrane. Under resting conditions, Mg2+ is evenly compartmentalized within mitochondria, nucleus and endo-sarco-plasmic reticulum (~16-18 mM within each of these compartments). An additional pool of Mg2+ is present in the cytoplasm, mostly in the form of a complex with ATP or other phospho-nucleotides (~5 mM). As a result of this partitioning/complexing, less than 1 mM is present as free [Mg2+] in the cytoplasm or within the mitochondria matrix.
The administration of adrenergic agonists to cardiac or liver cells markedly enhances Mg2+ extrusion via a cAMP-activated Na+-dependent process. Hormones that counteract adren-ceptor stimulation (e.g. vasopressin or insulin) prevent Mg2+ extrusion and/or promote the accumulation of a significant amount of Mg2+ within these cell types via protein kinase C signaling.
The ability of cardiac or liver cells to accumulate is specifically inhibited under pathological conditions such as diabetes (both type-I and type-II) or chronic alcohol consumption. Magnesium extrusion is also altered under these pathological conditions. In addition, both diabetes and alcohol consumption result in a marked decrease of cellular ATP level and cytoplasmic Mg2+ content.
The long term goal of my lab are: 1) to understand how cardiac and liver cells regulate Mg2+ transport and homeostasis under physiological conditions, and how these mechanisms are altered under diabetic conditions or following prolonged alcohol consumption, 2) to identify proteins specifically modified under diabetic conditions and following chronic alcohol consumption which affect Mg2+ homeostasis and transport, and 3) the short- and long-term implications of changes in cellular Mg2+ content for the operation of specific enzymes located within the mitochondria and the endo-sarco-plasmic reticulum.
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