Presynaptic P2X1-3 and ?3-containing nicotinic receptors assemble into functionally interacting ion channels in the rat hippocampus.
Previous studies documented a cross-talk between purinergic P2X (P2XR) and nicotinic acetylcholine receptors (nAChR) in heterologous expression systems and peripheral preparations. We now investigated if this occurred in native brain preparations and probed its physiological function. We found that P2XR and nAChR were enriched in hippocampal terminals, where both P2X1-3R ... and ?3, but not ?4, nAChR subunits were located in the active zone and in dopamine-?-hydroxylase-positive hippocampal terminals. Notably, P2XR ligands displaced nAChR binding and nAChR ligands displaced P2XR binding to hippocampal synaptosomes. In addition, a negative P2XR/nAChR cross-talk was observed in the control of the evoked release of noradrenaline from rat hippocampal synaptosomes, characterized by a less-than-additive facilitatory effect upon co-activation of both receptors. This activity-dependent cross-inhibition was confirmed in Xenopus oocytes transfected with P2X1-3Rs and ?3?2 (but not ?4?2) nAChR. Besides, P2X2 co-immunoprecipitated ?3?2 (but not ?4?2) nAChR, both in HEK cells and rat hippocampal membranes indicating that this functional interaction is supported by a physical association between P2XR and nAChR. Moreover, eliminating extracellular ATP with apyrase in hippocampal slices promoted the inhibitory effect of the nAChR antagonist tubocurarine on noradrenaline release induced by high- but not low-frequency stimulation. Overall, these results provide integrated biochemical, pharmacological and functional evidence showing that P2X1-3R and ?3?2 nAChR are physically and functionally interconnected at the presynaptic level to control excessive noradrenergic terminal activation upon intense synaptic firing in the hippocampus.
Mesh Terms:
Animals, Dopamine beta-Hydroxylase, HEK293 Cells, Hippocampus, Humans, Ion Channels, Male, Nerve Endings, Norepinephrine, Oocytes, Rats, Rats, Wistar, Receptor Cross-Talk, Receptors, Nicotinic, Receptors, Presynaptic, Receptors, Purinergic P2X, Receptors, Purinergic P2X1, Receptors, Purinergic P2X2, Receptors, Purinergic P2X3, Synaptosomes, Xenopus, alpha7 Nicotinic Acetylcholine Receptor
Animals, Dopamine beta-Hydroxylase, HEK293 Cells, Hippocampus, Humans, Ion Channels, Male, Nerve Endings, Norepinephrine, Oocytes, Rats, Rats, Wistar, Receptor Cross-Talk, Receptors, Nicotinic, Receptors, Presynaptic, Receptors, Purinergic P2X, Receptors, Purinergic P2X1, Receptors, Purinergic P2X2, Receptors, Purinergic P2X3, Synaptosomes, Xenopus, alpha7 Nicotinic Acetylcholine Receptor
Neuropharmacology
Date: Dec. 01, 2015
PubMed ID: 26801076
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