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是负责体感系统中冷传导的主要离子通道。TRPM8的神经末梢可用性决定了感冒敏感性，但对轴突分泌细胞器如何控制通道传递仍知之甚少。在这里，我们研究了冷敏感外周轴突中TRPM8和运输细胞器的分布，并通过药理学针对ARF-GEF GBF1或小GTPase RAB6来破坏运输。在坐骨神经的轴突中，GBF1的抑制会中断TRPM8的运输并增加与反式的联系-高尔基网络，LAMP1和高尔基卫星，它们沿轴突分布丰富。因此，在角膜冷热感受器的神经末梢中GBF1抑制后，TRPM8依赖性持续活动和冷诱发反应均可逆地下降。抑制RAB6（也与高尔基卫星相关）可降低体内感冒引起的反应。我们的结果支持非常规的轴突运输机制，控制轴突中TRPM8的可用性以及周围神经系统的冷敏感性。