TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption.
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-D28K, two divalent-binding proteins, are co-expressed 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.
Voets
Thomas
T
Department of Physiology, Campus Gasthuisberg, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. Thomas.Voets@med.kuleuven.ac.be
Nilius
Bernd
B
Hoefs
Susan
S
van der Kemp
Annemiete W C M
AW
Droogmans
Guy
G
Bindels
Rene J M
RJ
Hoenderop
Joost G J
JG
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D006996:Hypocalcemia / Q000235:genetics; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism*; D007668:Kidney / Q000502:physiology*; D007686:Kidney Tubules, Distal / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism*; D008275:Magnesium Deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008871:Microvilli / Q000378:metabolism; D008969:Molecular Sequence Data; D009399:Nephrons / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011994:Recombinant Proteins / Q000378:metabolism; D050053:TRPM Cation Channels; D014162:Transfection
D007473:Ion Channels; D010446:Peptide Fragments; D011994:Recombinant Proteins; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; D008274:Magnesium