Background and purpose: The aim of the present study was to investigate whether the endogenous metabotropic P2Y receptors modulate ionotropic P2X 3 receptor-channels. Experimental approach: Whole-cell patch-clamp experiments were carried out on HEK293 cells permanently transfected with human P2X 3 receptors (HEK293-hP2X 3 cells) and rat dorsal root ganglion (DRG) neurons. Key results: In both cell types, the P2Y 1,12,13 receptor agonist, ADP-β-S, inhibited P2X 3 currents evoked by the selective agonist, α,β-methylene ATP (α,β-meATP). This inhibition could be markedly counteracted by replacing in the pipette solution the usual GTP with GDP-β-S, a procedure known to block all G protein heterotrimers. P2X 3 currents evoked by ATP, activating both P2Y and P2X receptors, caused a smaller peak amplitude and desensitized faster than those currents evoked by the selective P2X 3 receptor agonist α,β-meATP. In the presence of intracellular GDP-β-S, ATP- and α,β-meATP-induced currents were identical. Recovery from P2X 3 receptor desensitization induced by repetitive ATP application was slower than the recovery from α,β-meATP-induced desensitization. When G proteins were blocked by intracellular GDP-β-S, the recovery from the ATP- and α,β-meATP-induced desensitization were of comparable speed. Conclusions and Implications: Our results suggest that the activation of P2Y receptors G protein-dependently facilitates the desensitization of P2X 3 receptors and suppresses the recovery from the desensitized state. Hence, the concomitant stimulation of P2X 3 and P2Y receptors of DRG neurons by ATP may result both in an algesic effect and a partly counterbalancing analgesic activity.
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