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Publications (2)6.73 Total impact

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    ABSTRACT: The transient receptor potential ankyrin 1 (TRPA1) channel is well known as a sensor to environmental irritant compounds, cold, and endogenous proalgesic agents. TRPA1 is expressed on sensory neurons and is involved in pain modulation. Etodolac is a cyclooxygenase (COX)-2 inhibitor that belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs). A recent study indicates that etodolac inhibits allyl isothiocyanate (AITC)-induced calcium influx in heterologous HEK293 cells and sensory neurons. To examine whether and how etodolac modulates the TRPA1 channels, we applied etodolac to TRPA1-transfected HEK293 cells or rat dorsal root ganglion (DRG) neurons and recorded the currents using the whole-cell patch clamp technique. We found that etodolac at higher doses could activate and then desensitize TRPA1 channels in heterologous expressing HEK293 cells as well as in DRG neurons. The etodolac-induced currents were significantly attenuated in cysteine residues mutated human TRPA1-transfected HEK293 cells. Interestingly, application of etodolac at drug plasma levels in clinical usage did not induce significant TRPA1 currents but reduced the subsequent AITC-induced currents to 25% in HEK293 cells expressing TRPA1. Moreover, no modulatory effect of etodolac on TRPA1 was detected in the cysteine mutant cells. These data indicate a novel mechanism of the anti-inflammatory and analgesic clinical effects of etodolac, which may be involved with its direct activation and the subsequent desensitization of TRPA1 through the covalent modification of cysteine residues. © 2013 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 08/2013; · 2.97 Impact Factor
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    ABSTRACT: 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.
    European Journal of Neuroscience 05/2012; 36(3):2293-301. · 3.75 Impact Factor