Feedback facilitation by adenosine A 2A receptors of ATP release from mouse hippocampal nerve terminals

The adenosine modulation system is mostly composed by inhibitory A 1 receptors (A 1 R) and the less abundant facilitatory A 2A receptors (A 2A R), the latter selectively engaged at high frequency stimulation associated with synaptic plasticity processes in the hippocampus. A 2A R 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 A 2A R 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 A 2A R knockout mice. The A 1 R agonist CPA (10-100 nM) inhibited ATP release, whereas the A 1 R 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 A 2A R, which are involved in an apparent feedback loop of A 2A R-mediated increased ATP release together with dampening of A 1 R-mediated inhibition. This study is a tribute to María Teresa Miras-Portugal.