Mg2+-homeostasis regulation in the immune system

As opposed to calcium the “signaling ion”, magnesium has commonly been described in literature as a “maintenance ion”. Despite the abundance and ubiquitous use of Mg2+ in all forms of life, and the well documented, crucial role of this cation in cellular physiology, extremely little is known about molecular components and mechanisms acting to regulate Mg2+-homeostasis, especially in vertebrates. Although there is still controversy whether cytosolic Mg2+ functions as a second messenger, over the last two decades, a growing number of studies in various cellular systems could demonstrate that Mg2+ homeostasis is a very dynamic process, with multiple and complex forms of regulation that probably plays an underestimated role in managing cell function and metabolism. It appears that TRPM7 is an essential Mg2+ uptake and sensing pathway, and therefore a key-component of these cellular processes.

TRPM7 (as well as its closest relative TRPM6) is a chanzyme, since it is the unique fusion of an ion channel with a kinase domain. We have shown that TRPM7 is a Ca2+/Mg2+ permeable channel whose activity is modulated by intracellular Mg2+ and Mg-nucleotides. Furthermore, the lethal phenotype caused by the inducible homozygous deletion of TRPM7 in the DT40 chicken B-lymphocytes can be totally reverted by supplementing the growth medium with mM concentrations of Mg2+. Amazingly, this phenotype is extremely similar to that of patients suffering from an inherited form of Hypomagnesemia who have been shown to bear mutations in TRPM6, the closest relative of TRPM7.

Ongoing projects in my lab aim to better understand the signaling network(s) underlying cellular Mg2+-homeostasis regulation, with a strong focus on the unique structural feature of TRPM7 and its kinase domain. We have constructed a series of cell lines stably and inducibly overexpressing TRPM7 kinase mutants, as well as isolated cytoplasmic TRPM7 domains. We are studying the effects of these mutations on channel function as well as on cellular physiology in the TRPM7-deficient DT40 cells. Our working hypothesis is that the TRPM7 channel and kinase activities are functionally linked, with the kinase modulating channel function, and the channel influencing kinase activity. In turn, the kinase might coordinate intracellular signaling pathways with the Mg2+-status of the cell. We are therefore also interested in identifying potential substrates of the TRPM7 kinase. Furthermore, we are investigating the effect of TRPM7-deficiency and Mg2+-homeostasis deregulation on B-cell receptor signaling.

Key Publications:

• Anne-Laure Perraud, Andrea Fleig, Chris A. Dunn, Leigh-Anne Bagley, Pierre Launay, Carsten Schmitz, Alex J. Stokes, Qiquin Zhu, Maurice J Bessman, Reinhold Penner, Jean-Pierre Kinet, and Andrew M. Scharenberg: ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature, 411 (6837), 595-9, 2001.
• Carsten Schmitz, Anne-Laure Perraud, Kazunori Inabe, Catherine O. Johnson, Megan K. Smith, Reinhold Penner, Tomohiro Kurosaki, Andrea Fleig, and Andrew M. Scharenberg: Regulation of vertebrate cellular Mg homeostasis by TRPM7. Cell (114), 191-200, 2003.
• Anne-Laure Perraud, Carsten Schmitz and Andrew M. Scharenberg: TRPM2 Ca2+ permeable cation channels: from gene to biological function. Cell Calcium 33, 519-531, 2003.
• Carsten Schmitz, Anne-Laure Perraud, Andrea Fleig and Andrew M. Scharenberg: Dual function ion channel/protein kinases: novel components of vertebrate Mg2+ regulatory mechanisms. Pediatric Research, 2004 55: 734-737.
• Ryuichi Takezawa, Carsten Schmitz, Philippe Demeuse, Andrew M. Scharenberg, Reinhold Penner and Andrea Fleig: Receptor-mediated regulation of TRPM7 channel through its endogenous protein kinase domain. Proc Natl Acad Sci U S A. 2004 Apr 20; 101(16): 6009-14.
• Perraud AL, Knowles HM, Schmitz C.: Novel aspects of signaling and ion-homeostasis regulation in immunocytes. The TRPM ion channels and their potential role in modulating the immune response. Mol Immunol. 2004 Jul;41(6-7):657-73.
• Schmitz C., Perraud A.-L.: The TRPM cation channels in the immune context, Curr Pharm Des, 2005;11(21):2765-78.
• Schmitz C., Dorovkov, M.V., Zhao X.Y., Davenport B,. Ryazanov A., Perraud A.-L.: The channel kinases TRPM6 and TRPM7 are functionally non-redundant. J Biol Chem. 2005: 11; 280(45):37763-71.
  

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