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Abstract
Interactions between calcium-activated chloride channel anoctamin 1 (ANO1) and transient receptor potential vanilloid 1 (TRPV1) enhance pain sensations in mice, suggesting that ANO1 inhibition could have analgesic effects. Here we show that menthol and the menthol analogue isopropylcyclohexane (iPr-CyH) inhibited ANO1 channels in mice. The iPr-CyH derivative 4-isopropylcyclohexanol (4-iPr-CyH-OH) inhibited mouse ANO1 currents more potently than iPr-CyH. Moreover, 4-iPr-CyH-OH inhibited the activities of TRPV1, TRP ankyrin 1 (TRPA1), TRP melastatin 8 (TRPM8) and TRPV4. Single-channel analysis revealed that 4-iPr-CyH-OH reduced TRPV1 and TRPA1 current open-times without affecting unitary amplitude or closed-time, suggesting that it affected gating rather than blocking the channel pore. The ability of 4-iPr-CyH-OH to inhibit action potential generation and reduce pain-related behaviors induced by capsaicin in mice suggests that 4-iPr-CyH-OH could have analgesic applications. Thus, 4-iPr-CyH-OH is a promising base chemical to develop novel analgesics that target ANO1 and TRP channels.
Highlights
Interactions between calcium-activated chloride channel anoctamin 1 (ANO1) and transient receptor potential vanilloid 1 (TRPV1) enhance pain sensations in mice, suggesting that ANO1 inhibition could have analgesic effects
Recent reports showed that the calcium-activated chloride channel anoctamin 1 (ANO1, known as TMEM16A), which is co-expressed with TRPV1 in dorsal root ganglia (DRG) neurons, is activated by calcium released from the endoplasmic reticulum and is sensitive to rapid noxious heating, making ANO1 another key factor in nociception[17,18,19,20,21]
In screens for other interactions of TRP channels with ANO1 in HEK293T cells, we found that 1 mM l-menthol, 500 μM carvacrol and 3 mM 2-aminoethoxydiphenylborane (2-APB) inhibited mouse ANO1 currents induced by 100 nM free calcium (Fig. 1a–c)
Summary
Interactions between calcium-activated chloride channel anoctamin 1 (ANO1) and transient receptor potential vanilloid 1 (TRPV1) enhance pain sensations in mice, suggesting that ANO1 inhibition could have analgesic effects. The ability of 4-iPr-CyH-OH to inhibit action potential generation and reduce pain-related behaviors induced by capsaicin in mice suggests that 4-iPr-CyH-OH could have analgesic applications. We showed that a known ANO1 inhibitor reduced TRPV1-mediated pain-related behaviors in mice[24] These results suggest that the apparent inward currents evoked by capsaicin in mouse sensory neurons have two components: TRPV1-mediated cationic inward currents and ANO1-mediated outward chloride currents, both of which contribute to the depolarization needed to generate action potentials. We attempted to find the basic chemical structure for menthol-mediated ANO1 inhibition and identified a novel analgesic compound, 4-isopropylcyclohexanol (4-iPr-CyH-OH), which acts on ANO1, TRPV1, TRPA1, TRPM8 and TRPV4
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