Lee Hyuk-Joon, Park Cheon-Gyu, Fedor Justin Gerald, Peele Wyatt A, Borgnia Mario J, Lee Seok-Yong
bioRxiv. 2025 Sep 11:2025.09.09.675254. doi: 10.1101/2025.09.09.675254.
The transient receptor potential melastatin member 8 (TRPM8) is a polymodal ion channel that senses cold and menthol in mammals. Despite prior structural studies, the mechanisms by which cold and menthol activate TRPM8 remain unresolved. Here, we present cryo-EM structures representing the cold and menthol-dependent activation trajectories, combined with extensive functional analyses. We captured snapshots of cooling-dependent pore opening, which involves dramatic pore rearrangement, suggesting a mechanism for cold sensing. Moreover, menthol binds dynamically to induce channel activation, which may underlie menthol specificity for TRPM8. Finally, we show how TRPM8 integrates multiple modalities (cold and menthol) through overlapping but non-identical pathways, revealing the temperature-specific "cold spot". These findings enhance our understanding of the molecular basis of physically and chemically induced cool sensation in mammals.
瞬时受体电位香草酸亚家族成员8（TRPM8）是一种多模式离子通道，可感知哺乳动物的寒冷和薄荷醇。尽管之前有结构研究，但寒冷和薄荷醇激活TRPM8的机制仍未解决。在这里，我们展示了代表寒冷和薄荷醇依赖性激活轨迹的冷冻电镜结构，并结合了广泛的功能分析。我们捕捉到了依赖于冷却的孔开放的快照，这涉及到显著的孔重排，提示了一种冷感机制。此外，薄荷醇动态结合以诱导通道激活，这可能是薄荷醇对TRPM8具有特异性的基础。最后，我们展示了TRPM8如何通过重叠但不相同的途径整合多种模式（寒冷和薄荷醇），揭示了温度特异性的“冷点”。这些发现增进了我们对哺乳动物中物理和化学诱导冷觉的分子基础的理解。
