UP FRONT MATTERS: Brief Review

Molecular Determinants of Magnesium Homeostasis: Insights from Human Disease

Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

¹ To whom correspondence should be addressed. E-mail: r.bindels{at}ncmls.ru.nl.

	Abstract

The past decade has witnessed multiple advances in our understanding of magnesium (Mg²⁺) homeostasis. The discovery that mutations in claudin-16/paracellin-1 or claudin-19 are responsible for familial hypomagnesemia with hypercalciuria and nephrocalcinosis provided insight into the molecular mechanisms governing paracellular transport of Mg²⁺. Our understanding of the transcellular movement of Mg²⁺ was similarly enhanced by the realization that defects in transient receptor potential melastatin 6 (TRPM6) cause hypomagnesemia with secondary hypocalcemia. This channel regulates the apical entry of Mg²⁺ into epithelia. In so doing, TRPM6 alters whole-body Mg²⁺ homeostasis by controlling urinary excretion. Consequently, investigation into the regulation of TRPM6 has increased. Acid-base status, 17 estradiol, and the immunosuppressive agents FK506 and cyclosporine affect plasma Mg²⁺ levels by altering TRPM6 expression. A mutation in epithelial growth factor is responsible for isolated autosomal recessive hypomagnesemia, and epithelial growth factor activates TRPM6. A defect in the -subunit of the Na,K-ATPase causes isolated dominant hypomagnesemia by altering TRPM6 activity through a decrease in the driving force for apical Mg²⁺ influx. We anticipate that the next decade will provide further detail into the control of the gatekeeper TRPM6 and, therefore, overall whole-body Mg²⁺ balance.