Editors' ChoiceNitric Oxide

No NOS Needed for This NO

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Science's STKE  25 Jul 2006:
Vol. 2006, Issue 345, pp. tw249
DOI: 10.1126/stke.3452006tw249

Nitric oxide is a potent signaling molecule in various physiological systems. Normally, its abundance is thought to be controlled through control of NO synthase (NOS) enzymes that produce NO. NO appears to serve several functions in the pancreas, but the literature contains conflicting reports on whether NOS is present in pancreatic acinar cells and whether NO generation is sensitive to changes in intracellular concentrations of free Ca2+. Chvanov et al. used fluorescent NO-sensitive dyes administered by patch clamping in cultured mouse pancreatic cells to explore NO signaling. They propose that the aforementioned confusion may arise in part because, to their surprise, NOS isn't the key source of NO signals in these cells. The authors could detect increased Ca2+-dependent production of NO in response to acetylcholine. Although pharmacological inhibitors of NOS did affect the later phase of this response (after about 600 seconds), the initial response (about 200 seconds after stimulation) was not affected. Chvanov et al. propose that this rapidly formed NO may come from previously bound cellular NO in the form of S-nitrosothiols. In keeping with this idea, treatment of cells with an NO donor (to increase intracellular S-nitrosothiol content) increased the generation of NO in response to high doses of acetylcholine. The authors estimate that release from S-nitrosothiols in these cells may provide about a 100-nM increase in NO concentration. Further studies with pharmacological inhibitors showed that the Ca2+ dependence of the NO response was not mediated by calmodulin or protein kinase C, but rather was sensitive to inhibitors of the Ca2+-sensitive protease calpain. The authors therefore speculate that this novel form of NO generation might result from partial proteolysis of S-nitrosylated proteins that reduces the stability of the S-NO bond and allows denitrosylation of thiol groups. Similar results in other mouse and bovine cell types indicated that the phenomenon is not restricted to pancreatic cells.

M. Chvanov, O. V. Gerasimenko, O. H. Petersen, A. V. Tepikin, Calcium-dependent release of NO from intracellular S-nitrosothiols. EMBO J. 25, 3024-3032 (2006). [PubMed]

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