Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel

Lizhen Xu, Yalan Han, Xiaoying Chen, Aerziguli Aierken, Han Wen, Wenjun Zheng, Hongkun Wang, Xiancui Lu, Zhenye Zhao, Cheng Ma, Ping Liang, Wei Yang (), Shilong Yang () and Fan Yang ()
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Lizhen Xu: Zhejiang University School of Medicine
Yalan Han: Kunming Institute of Zoology
Xiaoying Chen: Zhejiang University School of Medicine
Aerziguli Aierken: Zhejiang University School of Medicine
Han Wen: State University of New York at Buffalo
Wenjun Zheng: State University of New York at Buffalo
Hongkun Wang: Zhejiang University School of Medicine
Xiancui Lu: Kunming Institute of Zoology
Zhenye Zhao: Zhejiang University School of Medicine
Cheng Ma: Zhejiang University
Ping Liang: Zhejiang University School of Medicine
Wei Yang: Zhejiang University School of Medicine
Shilong Yang: Northeast Forestry University
Fan Yang: Zhejiang University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Menthol in mints elicits coolness sensation by selectively activating TRPM8 channel. Although structures of TRPM8 were determined in the apo and liganded states, the menthol-bounded state is unresolved. To understand how menthol activates the channel, we docked menthol to the channel and systematically validated our menthol binding models with thermodynamic mutant cycle analysis. We observed that menthol uses its hydroxyl group as a hand to specifically grab with R842, and its isopropyl group as legs to stand on I846 and L843. By imaging with fluorescent unnatural amino acid, we found that menthol binding induces wide-spread conformational rearrangements within the transmembrane domains. By Φ analysis based on single-channel recordings, we observed a temporal sequence of conformational changes in the S6 bundle crossing and the selectivity filter leading to channel activation. Therefore, our study suggested a ‘grab and stand’ mechanism of menthol binding and how menthol activates TRPM8 at the atomic level.

Date: 2020
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DOI: 10.1038/s41467-020-17582-x

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