Feedback facilitation by adenosine A receptors of ATP release from mouse hippocampal nerve terminals.

The adenosine modulation system is mostly composed by inhibitory A receptors (AR) and the less abundant facilitatory A receptors (AR), the latter selectively engaged at high frequency stimulation associated with synaptic plasticity processes in the hippocampus. AR are activated by adenosine originated from extracellular ATP through ecto-5'-nucleotidase or CD73-mediated catabolism. Using hippocampal synaptosomes, we now investigated how adenosine receptors modulate the synaptic release of ATP. The AR agonist CGS21680 (10-100 nM) enhanced the K-evoked release of ATP, whereas both SCH58261 and the CD73 inhibitor α,β-methylene ADP (100 μM) decreased ATP release; all these effects were abolished in forebrain AR knockout mice. The AR agonist CPA (10-100 nM) inhibited ATP release, whereas the AR antagonist DPCPX (100 nM) was devoid of effects. The presence of SCH58261 potentiated CPA-mediated ATP release and uncovered a facilitatory effect of DPCPX. Overall, these findings indicate that ATP release is predominantly controlled by AR, which are involved in an apparent feedback loop of AR-mediated increased ATP release together with dampening of AR-mediated inhibition. This study is a tribute to María Teresa Miras-Portugal.