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Peer-reviewedCC BY-NC-NDNature Communications

Molecular basis for cold and menthol sensing by mammalian TRPM8

  • Hyuk-Joon Lee1
  • Cheon-Gyu Park1
  • Justin G. Fedor1
  • Wyatt A. Peele2
  • Mario Juan Borgnia2
  • Seok‐Yong Lee3
  1. 1Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA
  2. 2Genome Integrity and Structural Biology Laboratory, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, USA
  3. 3Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA. [email protected]
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Abstract

The transient receptor potential melastatin member 8 (TRPM8) is a polymodal ion channel that senses cold and menthol in mammals. Despite prior structural studies, the mechanisms by which cold and menthol activate TRPM8 remain unresolved. Here, we present cryo-EM structures representing the cold and menthol-dependent activation trajectories, combined with extensive functional analyses. We captured snapshots of cooling-dependent pore opening, which involves dramatic pore rearrangement, suggesting a mechanism for cold sensing. Moreover, menthol binds dynamically to induce channel activation, which may underlie menthol specificity for TRPM8. Finally, we show how TRPM8 integrates multiple modalities (cold and menthol) through overlapping but non-identical pathways, revealing the temperature-specific “cold spot”. These findings enhance our understanding of the molecular basis of physically and chemically induced cool sensation in mammals.

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Cite

BibTeXRIS
BibTeX
@article{lee2026molecular,
  title = {{Molecular basis for cold and menthol sensing by mammalian TRPM8}},
  author = {Hyuk-Joon Lee and Cheon-Gyu Park and Justin G. Fedor and Wyatt A. Peele and Mario Juan Borgnia and Seok‐Yong Lee},
  journal = {Nature Communications},
  year = {2026},
  month = aug,
  doi = {10.1038/s41467-026-76926-1},
  url = {https://doi.org/10.1038/s41467-026-76926-1},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Molecular basis for cold and menthol sensing by mammalian TRPM8
AU  - Hyuk-Joon Lee
AU  - Cheon-Gyu Park
AU  - Justin G. Fedor
AU  - Wyatt A. Peele
AU  - Mario Juan Borgnia
AU  - Seok‐Yong Lee
PY  - 2026
DA  - 2026/08/17
JO  - Nature Communications
DO  - 10.1038/s41467-026-76926-1
UR  - https://doi.org/10.1038/s41467-026-76926-1
AB  - The transient receptor potential melastatin member 8 (TRPM8) is a polymodal ion channel that senses cold and menthol in mammals. Despite prior structural studies, the mechanisms by which cold and menthol activate TRPM8 remain unresolved. Here, we present cryo-EM structures representing the cold and menthol-dependent activation trajectories, combined with extensive functional analyses. We captured snapshots of cooling-dependent pore opening, which involves dramatic pore rearrangement, suggesting a mechanism for cold sensing. Moreover, menthol binds dynamically to induce channel activation, which may underlie menthol specificity for TRPM8. Finally, we show how TRPM8 integrates multiple modalities (cold and menthol) through overlapping but non-identical pathways, revealing the temperature-specific “cold spot”. These findings enhance our understanding of the molecular basis of physically and chemically induced cool sensation in mammals.
SN  - 2041-1723
ER  -