H(2)S functions as a nociceptive messenger through transient receptor potential ankyrin 1 (TRPA1) activation.
Hydrogen sulfide (H(2)S), an endogenous gasotransmitter, modulates various biological functions, including nociception. It is known that H(2)S causes neurogenic inflammation and elicits hyperalgesia. Here we show that H(2)S 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, H(2)S increased the intracellular Ca(2+) concentration ([Ca(2+)](i)), which was inhibited by ruthenium red (a nonselective TRP channel blocker) and HC-030031 (a TRPA1 blocker). H(2)S-responsive neurons highly corresponded to TRPA1 agonist-sensitive ones. [Ca(2+)](i) responses to H(2)S 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 H(2)S. H(2)S-induced [Ca(2+)](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 H(2)S. Intraplantar injection of H(2)S into the mouse hind paw caused acute pain which was significantly less in TRPA1(-/-) mice. The [Ca(2+)](i) responses to H(2)S in sensory neurons and in heterologously expressed channels, and pain-related behavior induced by H(2)S were enhanced under acidic conditions. These results suggest that H(2)S functions as a nociceptive messenger through the activation of TRPA1 channels. TRPA1 may be a therapeutic target for H(2)S-related algesic action, especially under inflammatory conditions.
Department of Veterinary Pharmacology, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan.
H
H
Ogawa
K
K
Takahashi
S
S
Miura
T
T
Imagawa
S
S
Saito
M
M
Tominaga
T
T
Ohta
D000818:Animals; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D059225:Nociception / Q000502:physiology*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
D018377:Neurotransmitter Agents; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D006862:Hydrogen Sulfide