Transient receptor potential (TRP) melastatin member 8 (TRPM8), which is a calcium-permeable ion channel, functions as the primary molecular sensor of cold and menthol in humans. Recent cryoelectron microscopy (cryo-EM) studies of TRPM8 have shown distinct structural features in its architecture and domain assembly compared with the capsaicin receptor TRP vanilloid member 1 (TRPV1). Moreover, ligand-bound TRPM8 structures have uncovered unforeseen binding sites for both cooling agonists and membrane lipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂]. These complex structures unveil the molecular basis of cooling agonist sensing by TRPM8 and the allosteric role of PI(4,5)P₂ in agonist binding for TRPM8 activation. Here, we review the recent advances in TRPM8 structural biology and investigate the molecular principles governing the distinguishing role of TRPM8 as the evolutionarily conserved menthol receptor.

瞬态受体电位 (TRP) melastatin member 8 (TRPM8) 是一种钙可渗透的离子通道，可作为人体寒冷和薄荷醇的主要分子传感器。与辣椒素受体 TRP vanilloid 成员 1 (TRPV1) 相比，最近对 TRPM8 的低温电子显微镜 (cryo-EM) 研究显示其结构和结构域组装具有明显的结构特征。此外，配体结合的 TRPM8 结构揭示了冷却激动剂和膜脂磷脂酰肌醇 4,5-二磷酸 [PI(4,5)P ₂ ] 的不可预见的结合位点。这些复杂的结构揭示了 TRPM8 感知冷却激动剂的分子基础和 PI(4,5)P _{2的变构作用}在 TRPM8 激活的激动剂结合中。在这里，我们回顾了 TRPM8 结构生物学的最新进展，并研究了控制 TRPM8 作为进化上保守的薄荷醇受体的独特作用的分子原理。