The channel kinases TRPM6 and TRPM7 are functionally nonredundant.
TRPM7 and its closest homologue, TRPM6, are the only known fusions of an ion channel pore with a kinase domain. Deletion of TRPM7 in DT40 B-lymphocytes causes growth arrest, Mg(2+) deficiency, and cell death within 24-48 h. Amazingly, in analogy to TRPM6-deficient patients who can live a normal life if provided with a Mg(2+)-rich diet, TRPM7-deficient DT40 B-lymphocytes show wild type cell growth if supplied with 5-10 mm Mg(2+) concentrations in their extracellular medium. Here we have investigated the functional relationship between TRPM6 and TRPM7. We show that TRPM7 deficiency in DT40 cells cannot be complemented by heterologously expressed TRPM6. Nevertheless, both channels can influence each other's biological activity. Our data demonstrate that TRPM6 requires TRPM7 for surface expression in HEK-293 cells and also that TRPM6 is capable of cross-phosphorylating TRPM7 as assessed using a phosphothreonine-specific antibody but not vice versa. TRPM6 and TRPM7 coexpression studies in DT40 B-cells indicate that TRPM6 can modulate TRPM7 function. In conclusion, although TRPM6 and TRPM7 are closely related and deficiency in either one of these molecules severely affects Mg(2+) homeostasis regulation, TRPM6 and TRPM7 do not appear to be functionally redundant but rather two unique and essential components of vertebrate ion homeostasis regulation.
Schmitz
Carsten
C
Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, 80206, USA.
Dorovkov
Maxim V
MV
Zhao
Xiaoyun
X
Davenport
Bennett J
BJ
Ryazanov
Alexey G
AG
Perraud
Anne-Laure
AL
D002455:Cell Division; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D006706:Homeostasis; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D008274:Magnesium