Feedback facilitation by adenosine A2A 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 alpha,beta-methylene ADP (100 mu M) 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 Maria Teresa Miras-Portugal.