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RECEPTORS AND SIGNAL TRANSDUCTION
Departments of 1Pediatrics, 2Microbiology and Immunology, 3Cellular and Molecular Physiology, 4Medicine, and 5Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; 6Division of Cellular and Molecular Biology, Ontario Cancer Institute, Toronto, Ontario, Canada; and 7Sigfried and Janet Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania
Submitted 28 April 2005 ; accepted in final form 18 November 2005
TRPM2 is a Ca2+-permeable channel activated by oxidative stress or TNF-
, and TRPM2 activation confers susceptibility to cell death. The mechanisms were examined here in human monocytic U937-ecoR cells. This cell line expresses full-length TRPM2 (TRPM2-L) and several isoforms including a short splice variant lacking the Ca2+-permeable pore region (TRPM2-S), which functions as a dominant negative. Treatment with H2O2, a model of oxidative stress, or TNF- results in reduced cell viability. Expression of TRPM2-L and TRPM2-S was modulated by retroviral infection. U937-ecoR cells expressing increased levels of TRPM2-L were treated with H2O2 or TNF-, and these cells exhibited significantly increased intracellular calcium concentration ([Ca2+]i), decreased viability, and increased apoptosis. A dramatic increase in cleavage of caspases-8, -9, -3, and -7 and poly(ADP-ribose)polymerase (PARP) was observed, demonstrating a downstream mechanism through which cell death is mediated. Bcl-2 levels were unchanged. Inhibition of the [Ca2+]i rise with the intracellular Ca2+ chelator BAPTA blocked caspase/PARP cleavage and cell death induced after activation of TRPM2-L, demonstrating the critical role of [Ca2+]i in mediating these effects. Downregulation of endogenous TRPM2 by RNA interference or increased expression of TRPM2-S inhibited the rise in [Ca2+]i, enhanced cell viability, and reduced numbers of apoptotic cells after exposure to oxidative stress or TNF-, demonstrating the physiological importance of TRPM2. Our data show that one mechanism through which oxidative stress or TNF- mediates cell death is activation of TRPM2, resulting in increased [Ca2+]i, followed by caspase activation and PARP cleavage. Inhibition of TRPM2-L function by reduction in TRPM2 levels, interaction with TRPM2-S, or Ca2+ chelation antagonizes this important cell death pathway.
oxidative stress; tumor necrosis factor-; apoptosis
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  J. Du, J. Xie, and L. Yue Intracellular calcium activates TRPM2 and its alternative spliced isoforms PNAS, April 28, 2009; 106(17): 7239 - 7244. [Abstract] [Full Text] [PDF]
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 A. Dietrich and T. Gudermann Another TRP to Endothelial Dysfunction: TRPM2 and Endothelial Permeability Circ. Res., February 15, 2008; 102(3): 275 - 277. [Full Text] [PDF]
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C. M. Hecquet, G. U. Ahmmed, S. M. Vogel, and A. B. Malik Role of TRPM2 Channel in Mediating H2O2-Induced Ca2+ Entry and Endothelial Hyperpermeability Circ. Res., February 15, 2008; 102(3): 347 - 355. [Abstract] [Full Text] [PDF]
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 W. Zhang, Q. Tong, K. Conrad, J. Wozney, J. Y. Cheung, and B. A. Miller Regulation of TRP channel TRPM2 by the tyrosine phosphatase PTPL1 Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1746 - C1758. [Abstract] [Full Text] [PDF]
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