title: Elucidating the role of the TRPM7 alpha-kinase: TRPM7 kinase inactivation leads to magnesium deprivation resistance phenotype in mice.
abstract: TRPM7 is an unusual bi-functional protein containing an ion channel covalently linked to a protein kinase domain. TRPM7 is implicated in regulating cellular and systemic magnesium homeostasis. While the biophysical properties of TRPM7 ion channel and its function are relatively well characterized, the function of the TRPM7 enzymatically active kinase domain is not understood yet. To investigate the physiological role of TRPM7 kinase activity, we constructed mice carrying an inactive TRPM7 kinase. We found that these mice were resistant to dietary magnesium deprivation, surviving three times longer than wild type mice; also they displayed decreased chemically induced allergic reaction. Interestingly, mutant mice have lower magnesium bone content compared to wild type mice when fed regular diet; unlike wild type mice, mutant mice placed on magnesium-depleted diet did not alter their bone magnesium content. Furthermore, mouse embryonic fibroblasts isolated from TRPM7 kinase-dead animals exhibited increased resistance to magnesium deprivation and oxidative stress. Finally, electrophysiological data revealed that the activity of the kinase-dead TRPM7 channel was not significantly altered. Together, our results suggest that TRPM7 kinase is a sensor of magnesium status and provides coordination of cellular and systemic responses to magnesium deprivation.
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Lillia V
authors.initials: LV
authors.lastname: Ryazanova
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Zhixian
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center and John A. Burns School of Medicine and Cancer Center, University of Hawaii, Honolulu, Hawaii 96813, USA.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Chubanov
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center and John A. Burns School of Medicine and Cancer Center, University of Hawaii, Honolulu, Hawaii 96813, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fleig
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Ryazanov
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000201:enzymology / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D008274:Magnesium / Q000378:metabolism; D008275:Magnesium Deficiency / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D018384:Oxidative Stress; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D050053:TRPM Cation Channels; D011494:Protein Kinases; C421903:Trpm7 protein, mouse; D008274:Magnesium