Inhibitory effect of polysulfide, an endogenous sulfur compound, on oxidative stress-induced TRPA1 activation.

Polysulfide (PS), an endogenous sulfur compound, generated by oxidation of hydrogen sulfide, has a stimulatory action on the nociceptive TRPA1 channel. TRPA1 is also activated by reactive oxygen species such as hydrogen peroxide (HO) produced during inflammation. Here, we examined the effect of PS on HO-induced responses in native and heterologously expressed TRPA1 using a cell-based calcium assay. We also carried out behavioral experiments in vivo. In mouse sensory neurons, HO elicited early TRPA1-dependent and late TRPA1-independent increases of [Ca]. The former was suppressed by the pretreatment with PS. In cells heterologously expressed TRPA1, PS suppressed [Ca] responses to HO. Simultaneous measurement of [Ca] and the intracellular PS level revealed that scavenging effect of PS was not related to the inhibitory effect. Removal of extracellular Ca, a calmodulin inhibitor and dithiothreitol attenuated the inhibitory effect of PS. Pretreatment with PS diminished nociceptive behaviors induced by HO. The present data suggest that PS suppresses oxidative stress-induced TRPA1 activation due to cysteine modification and Ca/calmodulin signaling. Thus, endogenous sulfurs may have regulatory roles in nociception via functional changes in TRPA1 under inflammatory conditions.