DataSheet1_Molecular determinants of TRPM8 function: key clues for a cool modulation.PDF

Cold thermoreceptor neurons detect temperature drops with highly sensitive molecular machinery concentrated in their peripheral free nerve endings. The main molecular entity responsible for cold transduction in these neurons is the thermo-TRP channel TRPM8. Cold, cooling compounds such as menthol, voltage, and osmolality rises activate this polymodal ion channel. Dysregulation of TRPM8 activity underlies several physiopathological conditions, including painful cold hypersensitivity in response to axonal damage, migraine, dry-eye disease, overactive bladder, and several forms of cancer. Although TRPM8 could be an attractive target for treating these highly prevalent diseases, there is still a need for potent and specific modulators potentially suitable for future clinical trials. This goal requires a complete understanding of the molecular determinants underlying TRPM8 activation by chemical and physical agonists, inhibition by antagonists, and the modulatory mechanisms behind its function to guide future and more successful treatment strategies. This review recapitulates information obtained from different mutagenesis approaches that have allowed the identification of specific amino acids in the cavity comprised of the S1-S4 and TRP domains that determine modulation by chemical ligands. In addition, we summarize different studies revealing specific regions within the N- and C-terminus and the transmembrane domain that contribute to cold-dependent TRPM8 gating. We also highlight the latest milestone in the field: cryo-electron microscopy structures of TRPM8, which have provided a better comprehension of the 21 years of extensive research in this ion channel, shedding light on the molecular bases underlying its modulation, and promoting the future rational design of novel drugs to selectively regulate abnormal TRPM8 activity under pathophysiological conditions.

冷热受体神经元通过其外围游离神经末梢高度敏感的分子机制检测温度下降。在这些神经元中，负责冷信号传导的主要分子实体为热敏TRP通道TRPM8。薄荷醇、冷却剂、电压和渗透压的升高能够激活这一多模态离子通道。TRPM8活动的失调是多种生理病理状态的基础，包括对轴突损伤引起的疼痛性冷过敏、偏头痛、干眼症、过度活跃的膀胱以及多种形式的癌症。尽管TRPM8可能成为治疗这些高发疾病的有吸引力的靶点，但仍需寻找强效且特异的调节剂，以备未来临床试验之用。实现此目标需要全面理解化学和物理激动剂诱导的TRPM8激活的分子决定因素、拮抗剂诱导的抑制以及其功能背后的调节机制，以指导未来的治疗策略并获得更成功的治疗效果。本文回顾了从不同突变方法中获得的信息，这些方法允许识别出由S1-S4和TRP域组成的腔室中的特定氨基酸，这些氨基酸决定了化学配体的调节作用。此外，我们总结了揭示N-和C-端以及跨膜域内特定区域的研究，这些区域对冷依赖性TRPM8门控有贡献。我们还强调了该领域的最新里程碑：TRPM8的冷冻电子显微镜结构，这些结构为21年来对这一离子通道的广泛研究提供了更深入的理解，揭示了其调节的分子基础，并促进了新型药物的未来理性设计，以选择性地调节病理生理条件下的异常TRPM8活性。