Department of Neuroscience and Biomedical Neuroscience Institute (BNI), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Department of Biology, Facultad de Química y Biología, Universidad de Santiago de Chile, and Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile.
Cell Rep. 2020 Mar 31;30(13):4505-4517.e5. doi: 10.1016/j.celrep.2020.03.017.
TRPM8 is the main ion channel responsible for cold transduction in the somatosensory system. Nerve terminal availability of TRPM8 determines cold sensitivity, but how axonal secretory organelles control channel delivery remains poorly understood. Here we examine the distribution of TRPM8 and trafficking organelles in cold-sensitive peripheral axons and disrupt trafficking by targeting the ARF-GEF GBF1 pharmacologically or the small GTPase RAB6 by optogenetics. In axons of the sciatic nerve, inhibition of GBF1 interrupts TRPM8 trafficking and increases association with the trans-Golgi network, LAMP1, and Golgi satellites, which distribute profusely along the axonal shaft. Accordingly, both TRPM8-dependent ongoing activity and cold-evoked responses reversibly decline upon GBF1 inhibition in nerve endings of corneal cold thermoreceptors. Inhibition of RAB6, which also associates to Golgi satellites, decreases cold-induced responses in vivo. Our results support a non-conventional axonal trafficking mechanism controlling the availability of TRPM8 in axons and cold sensitivity in the peripheral nervous system.
TRPM8 是躯体感觉系统中负责冷觉转导的主要离子通道。神经末梢 TRPM8 的可用性决定了冷敏性，但轴突分泌细胞器如何控制通道的输送仍知之甚少。本文中，我们研究了冷敏感外周轴突中 TRPM8 和运输细胞器的分布，并通过药理学靶向 ARF-GEF GBF1 或光遗传学靶向小 GTPase RAB6 来破坏运输。在坐骨神经轴突中，GBF1 的抑制会中断 TRPM8 的运输，并增加与顺式高尔基体网络、LAMP1 和高尔基体卫星的结合，后者沿着轴突轴广泛分布。因此，在角膜冷热敏感受器的神经末梢中，GBF1 抑制会使 TRPM8 依赖的持续活动和冷诱发反应可逆性下降。抑制也与高尔基体卫星结合的 RAB6，会使体内的冷诱导反应减少。我们的结果支持一种非传统的轴突运输机制，该机制控制着 TRPM8 在轴突中的可用性和周围神经系统的冷敏性。
