H2S functions as a nociceptive messenger through transient receptor potential ankyrin 1 (TRPA1) activation

Hydrogen sulfide (H2S), an endogenous gasotransmitter, modulates various biological functions, including nociception. It is known that H2S causes neurogenic inflammation and elicits hyperalgesia. Here we show that H2S activates mouse transient receptor potential ankyrin 1 (TRPA1) channels and elicits acute pain, using TRPA1-gene deficient mice (TRPA1(−/−)) and heterologous expression system. In wild-type mouse sensory neurons, H2S increased the intracellular Ca2+ concentration ([Ca2+]i), which was inhibited by ruthenium red (a nonselective TRP channel blocker) and HC-030031 (a TRPA1 blocker). H2S-responsive neurons highly corresponded to TRPA1 agonist-sensitive ones. [Ca2+]i responses to H2S were observed in neurons from transient receptor potential vanilloid 1 (TRPV1(−/−)) mice but not from TRPA1(−/−) mice. Heterologously expressed mouse TRPA1, but not mouse TRPV1, was activated by H2S. H2S-induced [Ca2+]i responses were inhibited by dithiothreitol, a reducing agent. Analyses of the TRPA1 mutant channel revealed that two cysteine residues located in the N-terminal internal domain were responsible for the activation by H2S. Intraplantar injection of H2S into the mouse hind paw caused acute pain which was significantly less in TRPA1(−/−) mice. The [Ca2+]i responses to H2S in sensory neurons and in heterologously expressed channels, and pain-related behavior induced by H2S were enhanced under acidic conditions. These results suggest that H2S functions as a nociceptive messenger through the activation of TRPA1 channels. TRPA1 may be a therapeutic target for H2S-related algesic action, especially under inflammatory conditions.

► In mouse sensory neurons, H2S evoked [Ca2+]i increases which were suppressed by TRPA1 antagonist. ► No response occurred by H2S in neurons of TRPA1−/− mice. ► Two cysteins located internal domain of TRPA1 channel may be the site of action. ► H2S evoked acute pain in wild-type, but not TRPA1−/− mice. ► External acid potentiated H2S actions.