Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), Okazaki, Aichi, Japan.
Adv Exp Med Biol. 2018;1099:29-36. doi: 10.1007/978-981-13-1756-9_3.
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.
初级感觉神经元通过位于质膜上的许多“传感器”蛋白来检测潜在的危险环境情况。虽然受体型阳离子通道被认为是感觉神经元中的主要传感器，但阴离子通道也是周围神经系统中的重要参与者。最近，我们表明瞬时受体电位香草酸 1 (TRPV1) 在初级感觉神经元中与anoctamin 1 (ANO1，也称为 TMEM16A)相互作用，这种相互作用增强了 TRPV1 介导的疼痛感觉。在该研究中，我们通过应用辣椒素来诱导小 DRG 神经元中的 ANO1 电流，并表明 TRPV1 激活后ANO1 依赖性去极化可以引发更多的动作电位。此外，ANO1 选择性阻断剂强烈抑制辣椒素诱发的小鼠疼痛相关行为。这些发现表明选择性 ANO1 抑制可以减轻疼痛感觉。我们还研究了非特异性抑制对离子通道活性的影响，以通过 TRPV1-ANO1 复合物控制离子动力学。我们发现 4-异丙基环己醇 (4-iPr-CyH-OH) 通过抑制 TRPV1 和 ANO1 共同对灼痛感觉具有镇痛作用。此外，4-iPr-CyH-OH 对 TRPV1、TRPA1 和 ANO1 活性的单独作用没有明显的激动作用。这些结果表明，4-iPr-CyH-OH 可以整体发挥作用，调节 TRP-ANO1 复合物的功能，以降低皮肤敏感性，并为新型镇痛剂奠定基础。
