TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption

被引:451
作者
Voets, T
Nilius, B
Hoefs, S
van der Kemp, AWCM
Droogmans, G
Bindels, RJM
Hoenderop, JGJ
机构
[1] Katholieke Univ Leuven, Dept Physiol, B-3000 Louvain, Belgium
[2] Univ Med Ctr Nijmegen, Nijmegen Ctr Mol Life Sci, Dept Physiol, NL-6500 HB Nijmegen, Netherlands
关键词
D O I
10.1074/jbc.M311201200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mg2+ is an essential ion involved in a multitude of physiological and biochemical processes and a major constituent of bone tissue. Mg2+ homeostasis in mammals depends on the equilibrium between intestinal Mg2+ absorption and renal Mg2+ excretion, but little is known about the molecular nature of the proteins involved in the transepithelial transport of Mg2+ in these organs. Recently, it was shown that patients with mutations in TRPM6, a member of the transient receptor potential family of cation channels, suffer from hypomagnesemia with secondary hypocalcemia (HSH) as a result of impaired renal and/or intestinal Mg2+ handling. Here, we show that TRPM6 is specifically localized along the apical membrane of the renal distal convoluted tubule and the brush-border membrane of the small intestine, epithelia particularly associated with active Mg2+ ( re) absorption. In kidney, parvalbumin and calbindin-D-28K, two divalent-binding proteins, are coexpressed with TRPM6 and might function as intracellular Mg2+ buffers in the distal convoluted tubule. Heterologous expression of wild-type TRPM6 but not TRPM6 mutants identified in HSH patients induces a Mg2+- and Ca2+-permeable cation channel tightly regulated by intracellular Mg2+ levels. The TRPM6-induced channel displays strong outward rectification, has a 5-fold higher affinity for Mg2+ than for Ca2+, and is blocked in a voltage-dependent manner by ruthenium red. Our data indicate that TRPM6 comprises all or part of the apical Mg2+ channel of Mg2+-absorbing epithelia.
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页码:19 / 25
页数:7
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