ATP signaling in brain: release, excitotoxicity and potential therapeutic targets

Adenosine 5'-triphosphate (ATP) is released as a genuine co-transmitter, or as a principal purinergic neurotransmitter, in an exocytotic and non-exocytotic manner. It activates ionotropic (P2X) and metabotropic (P2Y) receptors which mediate a plethora of functions in the brain. In particular, P2X7 receptor (P2X7R) are expressed in all brain cells and its activation can form a large pore allowing the passage of organic cations, the leakage of metabolites of up to 900 Da and the release of ATP itself. In turn, pannexins (Panx) are a family of proteins forming hemichannels that can release ATP. In this review, we summarize the progress in the understanding of the mechanisms of ATP release both in physiological and pathophysiological stages. We also provide data suggesting that P2X7R and pannexin 1 (Panx1) may form a large pore in cortical neurons as assessed by electrophysiology. Finally, the participation of calcium homeostasis modulator 1 is also suggested, another non-selective ion channel that can release ATP, and that could play a role in ischemic events, together with P2X7 and Panx1 during excitotoxicity by ATP.