P2X7 receptors exert a permissive role on the activation of release-enhancing presynaptic α7 nicotinic receptors co-existing on rat neocortex glutamatergic terminals

Adenosine triphosphate (ATP) has been reported to enhance the release of glutamate by acting at P2X presynaptic receptors. Acetylcholine (ACh) can elicit glutamate release through presynaptic nicotinic cholinergic receptors (nAChRs) of the α7 subtype situated on glutamatergic axon terminals, provided that the terminal membrane is weakly depolarized. Considering that ATP and ACh are co-transmitters, we here investigate on the possibility that P2X and nAChRs co-exist and interact on the same glutamatergic nerve endings using purified rat neocortex synaptosomes in superfusion. ATP evoked Ca2+-dependent release of preaccumulated d-[3H]aspartate ([3H]d-ASP) as well as of endogenous glutamate; (−)-nicotine, inactive on its own, potentiated the ATP-evoked release. The ATP analogue benzoylbenzoylATP (BzATP) behaved like ATP, but was ∼30 times more potent; the potentiation of the BzATP-evoked release was blocked by methyllycaconitine or α-bungarotoxin. Adding inactive concentrations of (−)-nicotine, epibatidine or choline together with inactive concentrations of BzATP resulted in significant elevation of the [3H]d-ASP release mediated by α7 nAChRs. To conclude, P2X7 receptors and α7 nAChRs seem to co-exist and interact on rat neocortex glutamatergic terminals; in particular, P2X7 receptors exert a permissive role on the activation of α7 nAChRs, suggesting that ATP may not only evoke glutamate release on its own, but may also regulate the release of the amino acid elicited by ACh.