Open AccessDisruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia
Author(s) -
Vladimir Chubanov,
Siegfried Waldegger,
Michael Mederos y Schnitzler,
Helga Vitzthum,
Martin Sassen,
Hannsjörg W. Seyberth,
Martin Konrad,
Thomas Gudermann
Publication year - 2004
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0305252101
Subject(s) - trpm7 , chemistry , hek 293 cells , heterologous expression , mutation , microbiology and biotechnology , missense mutation , gene , transient receptor potential channel , biology , biochemistry , receptor , recombinant dna
Impaired magnesium reabsorption in patients with TRPM6 gene mutations stresses an important role of TRPM6 (melastatin-related TRP cation channel) in epithelial magnesium transport. While attempting to isolate full-length TRPM6, we found that the human TRPM6 gene encodes multiple mRNA isoforms. Full-length TRPM6 variants failed to form functional channel complexes because they were retained intracellularly on heterologous expression in HEK 293 cells and Xenopus oocytes. However, TRPM6 specifically interacted with its closest homolog, the Mg(2+)-permeable cation channel TRPM7, resulting in the assembly of functional TRPM6/TRPM7 complexes at the cell surface. The naturally occurring S141L TRPM6 missense mutation abrogated the oligomeric assembly of TRPM6, thus providing a cell biological explanation for the human disease. Together, our data suggest an important contribution of TRPM6/TRPM7 heterooligomerization for the biological role of TRPM6 in epithelial magnesium absorption.