Feedback facilitation by adenosine A2A receptors of ATP release from mouse hippocampal nerve terminals

Abstract

The adenosine modulation system is mostly composed by inhibitory A1 receptors (A1R) and the less abundant facilitatory A2A receptors (A2AR), the latter selectively engaged at high frequency stimulation associated with synaptic plasticity processes in the hippocampus. A2AR 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 A2AR 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 A2AR knockout mice. The A1R agonist CPA (10-100 nM) inhibited ATP release, whereas the A1R 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 A2AR, which are involved in an apparent feedback loop of A2AR-mediated increased ATP release together with dampening of A1R-mediated inhibition. This study is a tribute to María Teresa Miras-Portugal.

Extracellular ATP inhibits excitatory synaptic input on parvalbumin positive interneurons and attenuates gamma oscillations via P2X4 receptors

“…Fast initial vesicular ATP release from astrocytes and neurons is followed by a more robust and longer secondary ATP release (Garré et al, 2010;Lalo & Pankratov, 2023). The vesicular release in the hippocampus is facilitated by presynaptic adenosine A 2A receptors activated after catabolism of extracellular ATP to adenosine (Gonçalves et al, 2023). The missing facilitation in the presence of the adenosine receptor blocker in our experiments might have lowered the extracellular ATP level and explain why the employed P2X antagonists and the knockout of the receptor did not affect gamma oscillations.…”