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

Abstract

The kidney is the principal organ responsible for the regulation of the body Mg(2+) balance. Identification of the gene defect in hypomagnesemia with secondary hypocalcemia recently elucidated transient receptor potential melastatin 6 (TRPM6) as the gatekeeper in transepithelial Mg(2+) transport, whereas its homolog, TRPM7, is implicated in cellular Mg(2+) homeostasis. The aim of this study was to determine the tissue distribution in mouse and regulation of TRPM6 and TRPM7 by dietary Mg(2+) and hormones. This study demonstrates that TRPM6 is expressed predominantly in kidney, lung, cecum, and colon, whereas TRPM7 is distributed ubiquitously. Dietary Mg(2+) restriction in mice resulted in hypomagnesemia and renal Mg(2+) and Ca(2+) conservation, whereas a Mg(2+)-enriched diet led to increased urinary Mg(2+) and Ca(2+) excretion. Conversely, Mg(2+) restriction significantly upregulated renal TRPM6 mRNA levels, whereas a Mg(2+) enriched diet increased TRPM6 mRNA expression in colon. Dietary Mg(2+) did not alter TRPM7 mRNA expression in mouse kidney and colon. In addition, it was demonstrated that 17beta-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 17beta-estradiol treatment normalized TRPM6 mRNA levels. In conclusion, kidney, lung, cecum, and colon likely constitute the main sites of active Mg(2+) (re)absorption in the mouse. In addition, Mg(2+) restriction and 17beta-estradiol upregulated renal TRPM6 mRNA levels, whereas a Mg(2+)-enriched diet stimulated TRPM6 mRNA expression in colon, supporting the gatekeeper function of TRPM6 in transepithelial Mg(2+) transport.