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 (H₂O₂) produced during inflammation. Here, we examined the effect of PS on H₂O₂-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, H₂O₂ elicited early TRPA1-dependent and late TRPA1-independent increases of [Ca²⁺]_i. The former was suppressed by the pretreatment with PS. In cells heterologously expressed TRPA1, PS suppressed [Ca²⁺]_i responses to H₂O₂. Simultaneous measurement of [Ca²⁺]_i and the intracellular PS level revealed that scavenging effect of PS was not related to the inhibitory effect. Removal of extracellular Ca²⁺, a calmodulin inhibitor and dithiothreitol attenuated the inhibitory effect of PS. Pretreatment with PS diminished nociceptive behaviors induced by H₂O₂. The present data suggest that PS suppresses oxidative stress-induced TRPA1 activation due to cysteine modification and Ca²⁺/calmodulin signaling. Thus, endogenous sulfurs may have regulatory roles in nociception via functional changes in TRPA1 under inflammatory conditions.