Instituto de Química Médica (IQM), CSIC, Madrid, Spain.
Med Res Rev. 2022 Nov;42(6):2168-2203. doi: 10.1002/med.21920. Epub 2022 Aug 17.
The cation nonselective channel TRPM8 is activated by multiple stimuli, including moderate cold and various chemical compounds (i.e., menthol and icilin [Fig. 1], among others). While research continues growing on the understanding of the physiological involvement of TRPM8 channels and their role in various pathological states, the information available on its activation mechanisms has also increased, supported by mutagenesis and structural studies. This review compiles known information on specific mutations of channel residues and their consequences on channel viability and function. Besides, the comparison of sequence of animals living in different environments, together with chimera and mutagenesis studies are helping to unravel the mechanism of adaptation to different temperatures. The results of mutagenesis studies, grouped by different channel regions, are compared with the current knowledge of TRPM8 structures obtained by cryo-electron microscopy. Trying to make this review self-explicative and highly informative, important residues for TRPM8 function are summarized in a figure, and mutants, deletions and chimeras are compiled in a table, including also the observed effects by different methods of activation and the corresponding references. The information provided by this review may also help in the design of new ligands for TRPM8, an interesting biological target for therapeutic intervention.
瞬时受体电位阳离子通道亚家族 M 成员 8（TRPM8）是一种非选择性阳离子通道，可被多种刺激激活，包括中等程度的寒冷刺激和多种化学化合物（如薄荷醇和异鼠李素[图 1]等）。虽然关于 TRPM8 通道的生理作用及其在各种病理状态中的作用的研究不断深入，但随着突变和结构研究的开展，有关其激活机制的信息也在不断增加。本综述汇总了有关通道残基特定突变及其对通道活力和功能影响的已知信息。此外，对生活在不同环境中的动物的序列进行比较，以及嵌合体和突变研究，有助于揭示对不同温度的适应机制。通过对不同通道区域的突变研究进行分组，并与低温电子显微镜获得的当前 TRPM8 结构知识进行比较。为了使本综述具有自我解释性和丰富的信息量，对 TRPM8 功能的重要残基进行了总结，并以表格形式列出了突变体、缺失体和嵌合体，包括不同激活方法的观察到的效果及其相应的参考文献。本综述提供的信息也有助于设计 TRPM8 的新型配体，TRPM8 是治疗干预的一个有趣的生物靶点。
