Inflammatory mediators potentiate ATP-gated channels through the P2X(3) subunit

The P2X(3) receptor is an ATP-gated ion channel predominantly expressed in nociceptive neurons from the dorsal root ganglion, P2X(3) receptor channels are highly expressed in sensory neurons and probably contribute to the sen sation of pain. Kinetics of P2X(3) currents are characterized by rapid dese nsitization (<100 ms) and slow recovery (>20 s). Thus, any mechanism modula ting rate of desensitization and/or recovery may have profound effect on su sceptibility of nociceptive neurons expressing P2X(3) to ATP, Here we show that currents mediated by P2X(3) receptor channels and the heteromeric chan nel P2X(2/3) composed of P2X(2) and P2X(3) subunits are potentiated by the neuropeptides substance P and bradykinin, which are known to modulate pain perception. The effect is mediated by the respective neuropeptide receptors , can be mimicked by phorbol ester and blocked by inhibitors of protein kin ases, Together with data from site-directed mutagenesis our results suggest that inflammatory mediators sensitize nociceptors through phosphorylation of P2X(3) and P2X(2/3) ion channels or associated proteins.