Magnesium (Mg²⁺), the second most abundant divalent intracellular cation, is involved in the vast majority of intracellular processes, including the synthesis of nucleic acids, proteins, and energy metabolism. The concentration of intracellular free Mg²⁺ ([Mg²⁺]_i) in mammalian cells is therefore tightly regulated to its optimum, mainly by an exchange of intracellular Mg²⁺ for extracellular Na⁺. Despite the importance of this process for cellular Mg²⁺ homeostasis, the gene(s) encoding for the functional Na⁺/Mg²⁺ exchanger is (are) still unknown. Here, using the fluorescent probe mag-fura 2 to measure [Mg²⁺]_i changes, we examine Mg²⁺ extrusion from hSLC41A1-overexpressing human embryonic kidney (HEK)-293 cells. A three- to fourfold elevation of [Mg²⁺]_i was accompanied by a five- to ninefold increase of Mg²⁺ efflux. The latter was strictly dependent on extracellular Na⁺ and reduced by 91% after complete replacement of Na⁺ with N-methyl-d-glucamine. Imipramine and quinidine, known unspecific Na⁺/Mg²⁺ exchanger inhibitors, led to a strong 88% to 100% inhibition of hSLC41A1-related Mg²⁺ extrusion. In addition, our data show regulation of the transport activity via phosphorylation by cAMP-dependent protein kinase A. As these are the typical characteristics of a Na⁺/Mg²⁺ exchanger, we conclude that the human SLC41A1 gene encodes for the Na⁺/Mg²⁺ exchanger, the predominant Mg²⁺ efflux system. Based on this finding, the analysis of Na⁺/Mg²⁺ exchanger regulation and its involvement in the pathogenesis of diseases such as Parkinson's disease and hypertension at the molecular level should now be possible.

Quinolones accumulate in cartilage, and because they form chelate complexes with divalent cations, they possess the potential to induce a deficiency of functionally available magnesium. To test the hypothesis that quinolone-induced arthropathy is caused (or aggravated) by magnesium deficiency in cartilage, we induced magnesium deficiency by feeding juvenile rats a magnesium-deficient diet for 9 days and treated the rats with single oral doses of ofloxacin (0, 100, 300, 600, or 1,200 mg/kg of body weight) during this period. Additional groups of juvenile rats on a normal diet were treated with ofloxacin correspondingly. Typical cartilage lesions (e.g., swollen matrix, cleft formation) were found in knee joints of all magnesium-deficient rats, including those without ofloxacin treatment. Lesions in these groups were not distinguishable from lesions induced by a single dose of 600 mg of ofloxacin per kg of body weight or higher in rats on a normal diet. Ofloxacin levels in plasma after 600 mg/kg of body weight were approximately 10-fold higher than those in humans during therapy with this quinolone. Lesions in rats treated with ofloxacin plus magnesium deficiency were more pronounced than those in rats with normal magnesium concentrations. After intake of a magnesium-deficient diet for 9 days, the magnesium concentration in serum (mean +/- standard deviation) was 0.18 +/- 0.05 mmol/liter (control on normal diet, 0.82 +/- 0.10 mmol/liter). Magnesium concentrations in bone (femur) and cartilage (processus xiphoideus) samples were 64.7 +/- 10.5 and 14.3 +/- 3.9 mmol/kg of dry weight, respectively, which corresponded to approximately 50% of the concentrations measured in controls on a normal diet. It was concluded that quinolone-induced arthropathy is probably caused by a deficit of available magnesium in joint cartilage due to the formation of quinolone-magnesium chelate complexes. If juvenile patients must be treated with quinolones for serious infections, it seems prudent to ensure that these patients do not have a disturbed magnesium balance.