Abstract
Magnesium (Mg2+) plays an essential role in many biological processes. Mg2+ deficiency is therefore associated with a wide range of clinical effects including muscle cramps, fatigue, seizures and arrhythmias. To maintain sufficient Mg2+ levels, (re)absorption of Mg2+ in the intestine and kidney is tightly regulated. Genetic defects that disturb Mg2+ uptake pathways, as well as drugs interfering with Mg2+ (re)absorption cause hypomagnesemia. The aim of this review is to provide an overview of the molecular mechanisms underlying genetic and drug-induced Mg2+ deficiencies. This leads to the identification of four main mechanisms that are affected by hypomagnesemia-causing mutations or drugs: luminal transient receptor potential melastatin type 6/7-mediated Mg2+ uptake, paracellular Mg2+ reabsorption in the thick ascending limb of Henle's loop, structural integrity of the distal convoluted tubule and Na+-dependent Mg2+ extrusion driven by the Na+/K+-ATPase. Our analysis demonstrates that genetic and drug-induced causes of hypomagnesemia share common molecular mechanisms. Targeting these shared pathways can lead to novel treatment options for patients with hypomagnesemia.
Highlights
Magnesium (Mg2+) plays an essential role in many biological processes
This leads to the identification of four main mechanisms that are affected by hypomagnesemia-causing mutations or drugs: luminal transient receptor potential melastatin type 6/7-mediated Mg2+ uptake, paracellular Mg2+ reabsorption in the thick ascending limb of Henle’s loop, structural integrity of the distal convoluted tubule and Na+-dependent Mg2+ extrusion driven by the Na+/K+-ATPase
Modest decreases in Mg2+ levels have been observed in animal models, indicating hypomagnesemia should not be completely ruled out in patients treated with EGF receptor (EGFR) tyrosine kinase inhibitors (TKI)[95,96]
Summary
Magnesium (Mg2+) plays an essential role in many biological processes. Mg2+ deficiency is associated with a wide range of clinical effects including muscle cramps, fatigue, seizures and arrhythmias. The aim of this review is to provide an overview of the molecular mechanisms underlying genetic and drug-induced Mg2+ deficiencies. Our analysis demonstrates that genetic and drug-induced causes of hypomagnesemia share common molecular mechanisms. Since the number of hypomagnesemia-causing mutations and drugs is steadily growing, the underlying mechanisms are becoming more elaborate and complex. Studying how these mechanisms are connected can help with finding the most important contributors to Mg2+ maintenance. The aim of this review is to provide an up-to-date overview of the molecular causes of genetic and drug-induced Mg2+ deficiencies and identify the main pathways of Mg2+ regulation shared between them
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