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J. Biol. Chem., Vol. 281, Issue 20, 14057-14065, May 19, 2006

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Metabolite of SIR2 Reaction Modulates TRPM2 Ion Channel^*

Olivera Grubisha, Louise A. Rafty¹, Christina L. Takanishi^¶, Xiaojie Xu, Lei Tong, Anne-Laure Perraud^¶, Andrew M. Scharenberg^¶2, and John M. Denu³

From the Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon 97239, the ^¶Department of Pediatrics and Immunology, University of Washington and Children's Hospital and Medical Center, Seattle, Washington 98195, and the Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53706

The transient receptor potential melastatin-related channel 2 (TRPM2) is a nonselective cation channel, whose prolonged activation by oxidative and nitrative agents leads to cell death. Here, we show that the drug puromycin selectively targets TRPM2-expressing cells, leading to cell death. Our data suggest that the silent information regulator 2 (Sir2 or sirtuin) family of enzymes mediates this susceptibility to cell death. Sirtuins are protein deacetylases that regulate gene expression, apoptosis, metabolism, and aging. These NAD⁺-dependent enzymes catalyze a reaction in which the acetyl group from substrate is transferred to the ADP-ribose portion of NAD⁺ to form deacetylated product, nicotinamide, and the metabolite OAADPr, whose functions remain elusive. Using cell-based assays and RNA interference, we show that puromycin-induced cell death is greatly diminished by nicotinamide (a potent sirtuin inhibitor), and by decreased expression of sirtuins SIRT2 and SIRT3. Furthermore, we demonstrate using channel current recordings and binding assays that OAADPr directly binds to the cytoplasmic domain of TRPM2 and activates the TRPM2 channel. ADP-ribose binds TRPM2 with similarly affinity, whereas NAD⁺ displays almost negligible binding. These studies provide the first evidence for the potential role of sirtuin-generated OAADPr in TRPM2 channel gating.

Received for publication, December 27, 2005 , and in revised form, March 24, 2006.

^* 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 Supported by a C. J. Martin Postdoctoral Research Fellowship 209667 (National Health and Medical Research Council of Australia).

² Supported by National Institutes of Health Grant GM64091.

³ Supported by National Institutes of Health Grant GM65386. To whom correspondence should be addressed: Dept. of Biomolecular Chemistry, University of Wisconsin-Medical School, 1300 University Ave., Madison, WI 53706. Tel.: 608-265-1859; Fax: 608-262-5253; E-mail: jmdenu{at}wisc.edu.

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