PDF《REQUEST.》

Static High-Gradient Magnetic Fields Activate Transient Receptor Potential Vanilloid

4 (TRPV4) Ion Channels Enabling Remote Control of Cell Function Oleg Lunov? , Vitalii Zablotskii? , Tatiana Syrovets? , Berthold Büchele? , Christoph Q.

Schmidt? , Alexandr Dejneka? , Damien Le Roy§ , Frederic Dumas- Bouchiat§ , Nora M. Dempsey§ , and Thomas Simmet?* From the ? Institute of Pharmacology of Natural Products &

Clinical Pharmacology, Ulm University, Ulm, 89081, Germany ? Institute of Physics, ASCR, Prague, 18221, Czech Republic § Institut Néel, CNRS/UJF, Grenoble, 38042, France * To whom correspondence should be addressed: Institute of Pharmacology of Natural Products &

Clinical Pharmacology, Ulm University, Helmholtzstr. 20, D-89081 Ulm, Germany. Tel.: +49-731-500-65600;

Fax: +49-731- 500-65602;

E-mail: thomas.simmet@uni- ulm.de. Running Title: Activation of TRPV4 channels by high-gradient magnetic fields Keywords: Magnetic field, cell differentiation, cell proliferation, intracellular calcium, mechanosensitive receptor Background: TRPV4 is a Ca2+ -permeable channel expressed in a number of cells and tissues. Results: Static high-gradient but not low- gradient magnetic fields activate TRPV4 channels. Conclusion: A novel mode of TRPV4 channel activation has been identified. Significance: Magnetic activation of TRPV4 channels enables remote control of cell function in the absence of chemical or biological agents. SUMMARY Biological effects of magnetic fields have been reported for some time, yet the molecular mechanisms procuring cellular responses remain obscure. A better understanding of the effects of magnetic fields on living cells will be instrumental for the development of new experimental and therapeutic strategies. Here, we identified a molecular effector of static high-gradient magnetic fields in human cells and we demonstrate that it can be used for the remote control of cellular transdifferentiation. High performance micro-magnet arrays generating spatially modulated high-gradient magnetic fields triggered the opening of transient receptor potential vanilloid

4 (TRPV4) ion channels in monocytic THP-1 cells and MRC-5 fibroblasts. Of note, the Ca2+ influx induced by high-gradient magnetic fields could not be mimicked by low-gradient magnetic fields produced by a conventional high- performance bulk magnet. Prolonged activation of the TRPV4 channels by high- gradient magnetic fields caused generation of radical oxygen species, inhibition of cell proliferation, and eventually apoptotic cell death. Signaling through elevated intracellular Ca2+ levels is crucial for cellular differentiation. Making use of this phenomenon, we demonstrate that activation of TRPV4 channels by transient exposure to high-gradient magnetic fields is sufficient to induce smooth muscle cell differentiation markers in fibroblasts indicating their differentiation into myofibroblasts. Thus, the spatially and temporally precisely controlled application of static high-gradient magnetic fields enables remote modulation of cell function and differentiation. Our findings reveal the mechanism how static high- gradient magnetic fields interfere with cell homeostasis and underscore that such THIS MANUSCRIPT HAS BEEN WITHDRAWN AT THE AUTHOR'

S REQUEST. http://www.jbc.org/cgi/doi/10.1074/jbc.M113.470914 The latest version is at JBC Papers in Press. Published on June 24,

2013 as Manuscript M113.470914 Copyright

2013 by The American Society for Biochemistry and Molecular Biology, Inc. by guest on October 22,

2018 http://www.jbc.org/ Downloaded from