Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia

Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2894-9. doi: 10.1073/pnas.0305252101. Epub 2004 Feb 19.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Cell Line
  • Cell Membrane / physiology
  • Cloning, Molecular
  • Female
  • Humans
  • Hypocalcemia / etiology
  • Hypocalcemia / genetics*
  • Ion Channels / genetics*
  • Ion Channels / physiology
  • Kinetics
  • Magnesium Deficiency / genetics*
  • Manganese / metabolism
  • Membrane Potentials / physiology
  • Membrane Proteins / genetics*
  • Membrane Proteins / physiology
  • Molecular Sequence Data
  • Mutation / genetics*
  • Oocytes / physiology
  • Protein Kinases / genetics*
  • Protein Kinases / physiology
  • Protein Serine-Threonine Kinases
  • Recombinant Proteins / metabolism
  • TRPM Cation Channels
  • Xenopus laevis

Substances

  • Ion Channels
  • Membrane Proteins
  • Recombinant Proteins
  • TRPM Cation Channels
  • TRPM6 protein, human
  • Manganese
  • Protein Kinases
  • Protein Serine-Threonine Kinases
  • TRPM7 protein, human

Associated data

  • GENBANK/AY333282
  • GENBANK/AY333283
  • GENBANK/AY333284
  • GENBANK/AY333285
  • GENBANK/AY333286
  • GENBANK/AY333287
  • GENBANK/AY333288
  • RefSeq/NM_021450