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J. Biol. Chem., Vol. 283, Issue 36, 24571-24583, September 5, 2008

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The Poly(ADP-ribose) Polymerase PARP-1 Is Required for Oxidative Stress-induced TRPM2 Activation in Lymphocytes^*

Ben Buelow, Yumei Song, and Andrew M. Scharenberg¹

From the Departments of Pediatrics and Immunology, University of Washington and Division of Immunology, Seattle Children's Hospital Research Institute, Seattle, Washington 98103

TRPM2 cation channels are widely expressed in the immune system and are thought to play a role in immune cell responses to oxidative stress. Patch clamp analyses suggest that TRPM2 channel activation can occur through a direct action of oxidants on TRPM2 channels or indirectly through the actions of a related group of adenine nucleotide 2nd messengers. However, the contribution of each gating mechanism to oxidative stress-induced TRPM2 activation in lymphocytes remains undefined. To better understand the molecular events leading to TRPM2 activation in lymphocytes, we analyzed oxidative stress-induced turnover of intracellular NAD, the metabolic precursor of adenine nucleotide 2nd messengers implicated in TRPM2 gating, and oxidative stress-induced TRPM2-mediated currents and Ca²⁺ transients in DT40 B cells. TRPM2-dependent Ca²⁺ entry did not influence the extent or time course of oxidative stress-induced turnover of NAD. Furthermore, expression of oxidative stress-activated poly(ADP-ribose) polymerases (PARPs) was required for oxidative stress-induced NAD turnover, TRPM2 currents, and TRPM2-dependent Ca²⁺ transients; no oxidant-induced activation of TRPM2 channels could be detected in PARP-deficient cells. Together, our results suggest that during conditions of oxidative stress in lymphocytes, TRPM2 acts as a downstream effector of the PARP/poly(ADP-ribose) glycohydrolase pathway through PARP-dependent formation of ADP-ribose.

Received for publication, April 7, 2008 , and in revised form, June 18, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Depts. of Pediatrics and Immunology, University of Washington and Seattle Children's Hospital Research Institute, Ste. 700, 1900 9th Ave., Seattle, WA 98103, E-mail: andrewms{at}u.washington.edu.

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