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CRON4healthyfuture
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 Posted: Sat Mar 25, 2006 12:52 am Post subject: Sir2/Sirtuin proteins regulate apoptosis and Ca channels |
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Interesting paper in the Journal of Biological Chemistry. This paper indicates that "O-acetylated ADP-ribose" produced during the catalytic cycle of the Sir2 decetylase family binds non-covalently to non-selective TRPM2 cation channels in the plasma membrane, which can understandably produce apoptosis.
However, a more physiologic role is posited by the investigators, one that suggests that activation of the Sir2 family of proteins may produce inward calcium currents that may produce physiologic effects that are less severe than apoptosis.
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| "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. " - Journal of Biological Chemistry, published online March 24, 2006 |
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