J. Neurochem. (2011) 118, 979–987.

Many organs express the extracellular 3′,5′‐cAMP‐adenosine pathway (conversion of extracellular 3′,5′‐cAMP to 5′‐AMP and 5′‐AMP to adenosine). Some organs release 2′,3′‐cAMP (isomer of 3′,5′‐cAMP) and convert extracellular 2′,3′‐cAMP to 2′‐ and 3′‐AMP and convert these AMPs to adenosine (extracellular 2′,3′‐cAMP‐adenosine pathway). As astrocytes and microglia are important participants in the response to brain injury and adenosine is an endogenous neuroprotectant, we investigated whether these extracellular cAMP‐adenosine pathways exist in these cell types. 2′,3′‐, 3′,5′‐cAMP, 5′‐, 3′‐, and 2′‐AMP were incubated with mouse primary astrocytes or primary microglia for 1 h and purine metabolites were measured in the medium by mass spectrometry. There was little evidence of a 3′,5′‐cAMP‐adenosine pathway in either astrocytes or microglia. In contrast, both cell types converted 2′,3′‐cAMP to 2′‐ and 3′‐AMP (with 2′‐AMP being the predominant product). Although both cell types converted 2′‐ and 3′‐AMP to adenosine, microglia were five‐ and sevenfold, respectively, more efficient than astrocytes in this regard. Inhibitor studies indicated that the conversion of 2′,3′‐cAMP to 2′‐AMP was mediated by a different ecto‐enzyme than that involved in the metabolism of 2′,3′‐cAMP to 3′‐AMP and that although CD73 mediates the conversion of 5′‐AMP to adenosine, an alternative ecto‐enzyme metabolizes 2′‐ or 3′‐AMP to adenosine.