The epithelial Mg2+ channel transient receptor potential melastatin 6 is regulated by dietary Mg2+ content and estrogens

The kidney is the principal organ responsible for the regulation of the body Mg2+ balance. Identification of the gene defect in hypomagnesemia with secondary hypocalcemia recently elucidated transient receptor potential melastatin 6 (TRPM6) as the gatekeeper in transepithelial Mg2+ transport, whereas its homolog, TRPM7, is implicated in cellular Mg2+ homeostasis. The aim of this study was to determine the tissue distribution in mouse and regulation of TRPM6 and TRPM7 by dietary Mg2+ and hormones. This study demonstrates that TRPM6 is expressed predominantly in kidney, lung, cecum, and colon, whereas TRPM7 is distributed ubiquitously. Dietary Mg2+ restriction in mice resulted in hypomagnesemia and renal Mg2+ and Ca2+ conservation, whereas a Mg2+-enriched diet led to increased urinary Mg2+ and Ca2+ excretion. Conversely, Mg2+ restriction significantly upregulated renal TRPM6 mRNA levels, whereas a Mg2+ enriched diet increased TRPM6 mRNA expression in colon. Dietary Mg2+ did not alter TRPM7 mRNA expression in mouse kidney and colon. In addition, it was demonstrated that 17 beta-estradiol but not 1,25-dihydroxyvitamin D-3 or parathyroid hormone regulates TRPM6 renal mRNA levels. Renal TRPM7 mRNA abundance remained unaltered under these conditions. The renal TRPM6 mRNA level in ovariectomized rats was significantly reduced, whereas 17 beta-estradiol treatment normalized TRPM6 mRNA levels. In conclusion, kidney, lung, cecum, and colon likely constitute the main sites of active Mg2+ (re)absorption in the mouse. In addition, Mg2+ restriction and 17 beta-estradiol upregulated renal TRPM6 mRNA levels, whereas a Mg2+-enriched diet stimulated TRPM6 mRNA expression in colon, supporting the gatekeeper function of TRPM6 in transepithelial Mg2+ transport.