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Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction

Author

Listed:
  • Xibao Liu

    (Secretory Physiology Section, National Cancer Institute, NIH)

  • Ana Cotrim

    (Translational Research Core, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Cancer Institute, NIH)

  • Leyla Teos

    (Secretory Physiology Section, National Cancer Institute, NIH)

  • Changyu Zheng

    (Translational Research Core, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Cancer Institute, NIH)

  • William Swaim

    (Secretory Physiology Section, National Cancer Institute, NIH)

  • James Mitchell

    (Radiation Biology Branch, National Cancer Institute, NIH)

  • Yasuo Mori

    (Laboratory of Molecular Biology, Graduate School of Engineering Kyoto University)

  • Indu Ambudkar

    (Secretory Physiology Section, National Cancer Institute, NIH)

Abstract

Xerostomia as a result of salivary gland damage is a permanent and debilitating side effect of radiotherapy for head and neck cancers. Effective treatments for protecting, or restoring, salivary gland function are not available. Here we report that irradiation treatment leads to activation of the calcium-permeable channel, transient potential melastatin-like 2 (TRPM2), via stimulation of poly-ADP-ribose polymerase. Importantly, irradiation induced an irreversible loss of salivary gland fluid secretion in TRPM2+/+ mice while a transient loss was seen in TRPM2−/− mice with >60% recovery by 30 days after irradiation. Treatment of TRPM2+/+ mice with the free radical scavenger Tempol or the PARP1 inhibitor 3-aminobenzamide attenuated irradiation-induced activation of TRPM2 and induced significant recovery of salivary fluid secretion. Furthermore, TPL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) induced complete recovery of function in irradiated TRPM2−/− mice. These novel data demonstrate that TRPM2 is activated by irradiation, via PARP1 activation, and contributes to irreversible loss of salivary gland function.

Suggested Citation

  • Xibao Liu & Ana Cotrim & Leyla Teos & Changyu Zheng & William Swaim & James Mitchell & Yasuo Mori & Indu Ambudkar, 2013. "Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction," Nature Communications, Nature, vol. 4(1), pages 1-10, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2526
    DOI: 10.1038/ncomms2526
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