Metabolite of SIR2 reaction modulates TRPM2 ion channel

doi:10.1074/jbc.M513741200

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Papers In Press, published online ahead of print March 24, 2006
J. Biol. Chem, 10.1074/jbc.M513741200
Submitted on December 27, 2005
Revised on March 24, 2006
Accepted on March 24, 2006

Metabolite of SIR2 reaction modulates TRPM2 ion channel

Olivera Grubisha, Louise A. Rafty, Christina L. Takanishi, Xiaojie Xu, Lei Tong, Anne-Laure Perraud, Andrew M. Scharenberg, and John M. Denu

Biomolecular Chemistry, University of Wisconsin Medical School, Madison, WI 53706

Corresponding Author: jmdenu{at}wisc.edu

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. Sir2 proteins 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 O-acetyl-ADP-ribose, OAADPr, whose functions remain elusive. Using cell-based assays, RNA interference, channel current recordings, and direct binding assays, we show that OAADPr directly binds and activates the TRPM2 channel. Puromycin-induced cell death was greatly diminished by nicotinamide (a potent sirtuin inhibitor) and by decreased expression of sirtuins SIRT2 and SIRT3. OAADPr directly binds to the cytoplasmic domain of the TRPM2 channel. ADP-ribose was shown to bind with similarly affinity, while NAD displayed almost negligible binding. These studies provide the first evidence for the potential role of sirtuin-generated OAADPr in TRPM2 channel gating.

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