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The Journal of Neuroscience, August 15, 2000, 20(16):6294-6301

Nitric Oxide-Stimulated Increase in Extracellular Adenosine Accumulation in Rat Forebrain Neurons in Culture Is Associated with ATP Hydrolysis and Inhibition of Adenosine Kinase Activity

Paul A. Rosenberg, Ya Li, Minou Le, and Yumin Zhang

Department of Neurology and Program in Neuroscience, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Adenosine is a putative endogenous sleep-inducing substance, and nitric oxide has been implicated in arousal and sleep mechanisms. We found that various nitric oxide donors, including diethylamine NONOate (DEA/NO), stimulated large increases in extracellular adenosine in nearly pure cultures of forebrain neurons. The effect of DEA/NO could be blocked by 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-oxide and could not be mimicked by degraded solutions of DEA/NO or by DEA itself; therefore, it was caused by nitric oxide release on hydrolysis of the parent compound. The accumulation of adenosine was not blocked by probenecid or GMP, suggesting that neither extracellular cAMP nor extracellular AMP was the source, and that adenosine was therefore the most likely species transported across the plasma membrane. To pursue this further, we tested the effect of DEA/NO on cellular ATP and found a significant fall in ATP associated with exposure to nitric oxide. In addition, exposure to DEA/NO nearly completely inhibited adenosine kinase activity. It has been found previously that adenosine kinase is inhibited by its substrate, adenosine. We found that exposure to nitric oxide increased intracellular adenosine to 125 ± 18% of control values (p < 0.01), consistent with the possibility that in our system the inhibition of adenosine kinase is related to an increase in intracellular adenosine, and that the effect of nitric oxide on extracellular adenosine is significantly potentiated by substrate inhibition of adenosine kinase. Furthermore, nitric oxide-stimulated adenosine accumulation may be important in the regulation of behavioral state.

Key words: nitric oxide; adenosine; sleep; adenosine kinase; ATP; laterodorsal tegmental nucleus; pedunculopontine tegmental nucleus

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20166294-08$05.00/0

This article has been cited by other articles:

				C. Ribelayga and S. C. Mangel A Circadian Clock and Light/Dark Adaptation Differentially Regulate Adenosine in the Mammalian Retina J. Neurosci., January 5, 2005; 25(1): 215 - 222. [Abstract] [Full Text] [PDF]

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