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<p>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 <i>Trpm8</i> gene in mice, introducing a single point mutation to render them insensitive to coldness.</p>

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Rational tuning of temperature sensitivity of the TRPM8 channel

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月14日

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

摘要

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.