Role of CNPase in the oligodendrocytic extracellular 2,3-cAMP-adenosine pathway

Extracellular adenosine 3,5-cyclic monophosphate (3,5-cAMP) is an endogenous source of localized adenosine production in many organs. Recent studies suggest that extracellular 2,3-cAMP (positional isomer of 3,5-cAMP) is also a source of adenosine, particularly in the brain in vivo post-injury. Moreover, in vitro studies show that both microglia and astrocytes can convert extracellular 2,3-cAMP to adenosine. Here, we examined the ability of primary mouse oligodendrocytes and neurons to metabolize extracellular 2,3-cAMP and their respective adenosine monophosphates (2-AMP and 3-AMP). Cells were also isolated from mice deficient in 2,3-cyclic nucleotide-3-phosphodiesterase (CNPase). Oligodendrocytes metabolized 2,3-cAMP to 2-AMP with 10-fold greater efficiency than did neurons (and also more than previously examined microglia and astrocytes); whereas, the production of 3-AMP was minimal in both oligodendrocytes and neurons. The production of 2-AMP from 2,3-cAMP was reduced by 65% in CNPase -/- versus CNPase +/+ oligodendrocytes. Oligodendrocytes also converted 2-AMP to adenosine, and this was also attenuated in CNPase -/- oligodendrocytes. Inhibition of classic 3,5-cAMP-3-phosphodiesterases with 3-isobutyl-1-methylxanthine did not block metabolism of 2,3-cAMP to 2-AMP and inhibition of classic ecto-5-nucleotidase (CD73) with ,-methylene-adenosine-5-diphosphate did not attenuate the conversion of 2-AMP to adenosine. These studies demonstrate that oligodendrocytes express the extracellular 2,3-cAMP-adenosine pathway (2,3-cAMP 2-AMP adenosine). This pathway is more robustly expressed in oligodendrocytes than in all other CNS cell types because CNPase is the predominant enzyme that metabolizes 2,3-cAMP to 2-AMP in CNS cells. By reducing levels of 2,3-cAMP (a mitochondrial toxin) and increasing levels of adenosine (a neuroprotectant), oligodendrocytes may protect axons from injury. GLIA 2013;61:1595-1606