Involvement of TRPV1-ANO1 Interactions in Pain-Enhancing Mechanisms
Primary sensory neurons detect potentially dangerous environmental situations via many “sensor” proteins located on the plasma membrane. Although receptor-type cation channels are thought to be the major sensors in sensory neurons, anion channels are also important players in the peripheral nervous system. Recently, we showed that transient receptor potential vanilloid 1 (TRPV1) interacts with anoctamin 1 (ANO1, also called TMEM16A) in primary sensory neurons and that this interaction enhanced TRPV1-mediated pain sensation. In that study, we induced ANO1 currents by application of capsaicin to small DRG neurons and showed that ANO1-dependent depolarization following TRPV1 activation could evoke more action potentials. Furthermore, capsaicin-evoked pain-related behaviors in mice were strongly inhibited by a selective ANO1 blocker. Together these findings indicate that selective ANO1 inhibition can reduce pain sensation. We also investigated non-specific inhibitory effects on ion channel activities to control ion dynamics via the TRPV1-ANO1 complex. We found that 4-isopropylcyclohexanol (4-iPr-CyH-OH) had an analgesic effect on burning pain sensations through its inhibition of TRPV1 and ANO1 together. Additionally, 4-iPr-CyH-OH did not have clear agonistic effects on TRPV1, TRPA1, and ANO1 activity individually. These results indicate that 4-iPr-CyH-OH could function globally to mediate TRP-ANO1 complex functions to reduce skin hypersensitivity and could form the basis for novel analgesic agents.
KeywordsTRP channel Anoctamin 1 Isopropylcyclohexanol Acute pain
Our study is supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan, the Kato Memorial Bioscience Foundation, and the Takeda Science Foundation.
- 11.Jin X, Shah S, Liu Y, Zhang H, Lees M, Fu Z, Lippiat JD, Beech DJ, Sivaprasadarao A, Baldwin SA, Zhang H, Gamper N (2013) Activation of the Cl- channel ANO1 by localized calcium signals in nociceptive sensory neurons requires coupling with the IP3 receptor. Sci Signal 6:ra73CrossRefPubMedCentralGoogle Scholar
- 21.Maruyama K, Takayama Y, Kondo T, Ishibashi KI, Sahoo BR, Kanemaru H, Kumagai Y, Martino MM, Tanaka H, Ohno N, Iwakura Y, Takemura N, Tominaga M, Akira S (2017) Nociceptors boost the resolution of fungal osteoinflammation via the TRP channel-CGRP-Jdp2 axis. Cell Rep 19:2730–2742CrossRefPubMedCentralGoogle Scholar