title: Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction.
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.
authors: Secretory Physiology Section, National Cancer Institute, NIH, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
authors: Xibao
authors: X
authors: Liu
authors: Ana
authors: A
authors: Cotrim
authors: Leyla
authors: L
authors: Teos
authors: Changyu
authors: C
authors: Zheng
authors: William
authors: W
authors: Swaim
authors: James
authors: J
authors: Mitchell
authors: Yasuo
authors: Y
authors: Mori
authors: Indu
authors: I
authors: Ambudkar
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011832:Radiation Injuries / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D012463:Saliva / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D012469:Salivary Glands / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000528:radiation effects*; D012472:Salivation / Q000187:drug effects / Q000528:radiation effects; D013363:Submandibular Gland / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D050053:TRPM Cation Channels / Q000172:deficiency* / Q000378:metabolism; D014965:X-Rays
chemical_list: C110289:4-hydroxy-2,2,6,6--tetramethylpiperidine-1-N-hydroxyl; D001549:Benzamides; D004791:Enzyme Inhibitors; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; C544443:TRPM2 protein, mouse; C025160:3-aminobenzamide; D002217:Carbachol; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; D002118:Calcium