Rational tuning of temperature sensitivity of the TRPM8 channel

Detecting temperature is crucial for the survival of living organisms. Although the temperature sensitive Transient Receptor Potential Melastatin 8 (TRPM8) channel has been identified as the prototypical cold sensor, the mechanisms by which it detects temperature remain elusive. In this study, we first identify groups of clustered residues that undergo conformational rearrangements between buried and exposed states during cold activation by hydroxyl radical footprinting-mass spectrometry (HRF-MS). By systematically perturbing water-protein interactions at these residues with point mutations that change side chain hydrophobicity (SCH), we achieve rational tuning of temperature sensitivity in this channel. Specifically, mutations with the clearest impacts on TRPM8 cold sensitivity are clustered in the MHR1-3 domains, where the protein of isolated MHR1-3 domains also exhibits clear conformational rearrangements in response to cold. Guided by this mechanism, we rationally edit the Trpm8 gene in mice, introducing a single point mutation to render them insensitive to coldness.

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Publication Details

Journal
EMBO Reports
Published
2025-11-14
DOI
https://doi.org/10.1038/s44319-025-00630-2
Primary Topic
Ion Channels and Receptors
Type
article
Field-Weighted Citation Impact
0.00
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article

Rational tuning of temperature sensitivity of the TRPM8 channel

Tiannan Guo, Han Wen, Shilong Yang, Wei Yang et al.
EMBO Reports
Ion Channels and Receptors
article

Rational tuning of temperature sensitivity of the TRPM8 channel

Tiannan Guo, Han Wen, Shilong Yang, Wei Yang, Zhangzhi Xue, Yi Zhu, Xiao Yi, Fan Yang, Wenxuan Zhen, Zhenfeng Deng, Xiao Liang, Bei Li, Bing Zhang, Yunfei Wang, Xiaoying Chen, Fangfei Zhang, Lizhen Xu, Lidan Hu
article en

Abstract

Detecting temperature is crucial for the survival of living organisms. Although the temperature sensitive Transient Receptor Potential Melastatin 8 (TRPM8) channel has been identified as the prototypical cold sensor, the mechanisms by which it detects temperature remain elusive. In this study, we first identify groups of clustered residues that undergo conformational rearrangements between buried and exposed states during cold activation by hydroxyl radical footprinting-mass spectrometry (HRF-MS). By systematically perturbing water-protein interactions at these residues with point mutations that change side chain hydrophobicity (SCH), we achieve rational tuning of temperature sensitivity in this channel. Specifically, mutations with the clearest impacts on TRPM8 cold sensitivity are clustered in the MHR1-3 domains, where the protein of isolated MHR1-3 domains also exhibits clear conformational rearrangements in response to cold. Guided by this mechanism, we rationally edit the Trpm8 gene in mice, introducing a single point mutation to render them insensitive to coldness.

EMBO ReportsVol. 26(24)
Zhejiang Chinese Medical University (CN), Westlake University (CN), Children's Hospital of Zhejiang University (CN), First Affiliated Hospital Zhejiang University (CN), Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, Alibaba Group (China) (CN), Northeast Forestry University (CN), Zhejiang University (CN)
Openalex Percentile: Top 66%
Ion Channels and Receptors
DOIOpen Access PDFOpenAlex
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