Premium
Potentiation of the P2X3 ATP receptor by PAR‐2 in rat dorsal root ganglia neurons, through protein kinase‐dependent mechanisms, contributes to inflammatory pain
Author(s) -
Wang Shenglan,
Dai Yi,
Kobayashi Kimiko,
Zhu Wanjun,
Kogure Yoko,
Yamanaka Hiroki,
Wan You,
Zhang Wensheng,
Noguchi Koichi
Publication year - 2012
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2012.08142.x
Subject(s) - long term potentiation , protein kinase a , microbiology and biotechnology , phosphorylation , ionotropic effect , protein kinase c , kinase , signal transduction , receptor , agonist , chemistry , biology , biochemistry , glutamate receptor
Proinflammatory agents trypsin and mast cell tryptase cleave and activate protease‐activated receptor‐2 (PAR‐2), which is expressed on sensory nerves and causes 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 α, β, 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 extracellular signal‐regulated kinases (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.