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

doi:10.1073/pnas.0305252101

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

^*Institute for Pharmacology and Toxicology, Philipps University Marburg, 35033 Marburg, Germany; ^†University Children's Hospital, Philipps University Marburg, 35037 Marburg, Germany; and ^‡Department of Physiology I, University of Regensburg, 93040 Regensburg, Germany

Edited by Lily Y. Jan, University of California School of Medicine, San Francisco, CA (received for review August 15, 2003)

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 Mg²⁺-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.

Footnotes

↵ § To whom correspondence should be addressed at: Institute for Pharmacology and Toxicology, Philipps University Marburg, Karl-von-Frisch Strasse 1, 35033 Marburg, Germany. E-mail: guderman{at}staff.uni-marburg.de.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: CFP, cyan fluorescent protein; FRET, fluorescence resonance energy transfer; HSH, hypomagnesemia with secondary hypocalcemia; YFP, yellow fluorescent protein.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database [accession nos. AY333282 (TRPM6a), AY333283 (TRPM6b), AY333284 (TRPM6c), AY333285 (TRPM6a-t), AY333286 (M6-kinase 1), AY333287 (M6-kinase 2), AY333288 (M6-kinase 3), and NM_021450 (TRPM7)].