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Shenglan Wang, Yi Dai, Kimiko Kobayashi, Wanjun Zhu, Yoko Kogure, Hiroki Yamanaka, You Wan, Wensheng Zhang and Koichi Noguchi Potentiation of the P2X3 ATP receptor by PAR-2 in rat dorsal root ganglia neurons, through protein kinase-dependent mechanisms, contributes to inflammatory pain European Journal of Neuroscience 36

Version of Record online: 23 MAY 2012 | DOI: 10.1111/j.1460-9568.2012.08142.x

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Proinflammatory agents trypsin and mast cell tryptase cleave and activate protease-activated receptor-2 (PAR-2), which is expressed on sensory nerves and cause neurogenic inflammation. P2X3 is a subtype of the ionotropic receptors for adenosine 5′-triphosphate (ATP) and is mainly localized on nociceptors. Here, we show that a functional interaction of the PAR-2 and P2X3 in primary sensory neurons could contribute to inflammatory pain. PAR-2 activation increased the P2X3 currents evoked by alpha beta-methylene ATP in dorsal root ganglia (DRG) neurons. Application of inhibitors of either protein kinase C (PKC) or protein kinase A (PKA) suppressed this potentiation. Consistent with this, a PKC or PKA activator mimicked the PAR-2 mediated potentiation of P2X3 currents. In the in vitro phosphorylation experiments, application of a PAR-2 agonist failed to establish phosphorylation of the P2X3 either on the serine or the threonine site. In contrast, application of a PAR-2 agonist induced trafficking of the P2X3 from the cytoplasm to the plasma membrane. These findings indicate that PAR-2 agonists may potentiate the P2X3, and the mechanism of this potentiation is likely to be a result of translocation, but not phosphorylation. The functional interaction between P2X3 and PAR-2 was also confirmed by detection of the α,β,methylene-ATP-evoked ERK activation, a marker of neuronal signal transduction in DRG neurons, and pain behavior. These results demonstrate a functional interaction of the protease signal with the ATP signal, and a novel mechanism through which protease released in response to tissue inflammation might trigger the sensation to pain through P2X3 activation.

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