9zyr | pdb_00009zyr
Menthol-and PIP2-bound mouse TRPM8 in a closed (C1M) state
Structural highlights
FunctionTRPM8_MOUSE Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalyptol, menthol, cold and modulation of intracellular pH. Involved in menthol sensation. Permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. Temperature sensing is tightly linked to voltage-dependent gating. Activated upon depolarization, changes in temperature resulting in graded shifts of its voltage-dependent activation curves. The chemical agonists menthol functions as a gating modifier, shifting activation curves towards physiological membrane potentials. Temperature sensitivity arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing.[1] [2] Publication Abstract from PubMedThe 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 and extensive functional analyses to reveal cold- and menthol-dependent activation mechanisms. We observe that cold-sensing residues are widespread and that snapshots of cooling-dependent opening reveal dramatic pore rearrangement which suggest a mechanism for cold sensing. Menthol binds dynamically to drive channel activation toward a common gate with cold, but with specific outer pore conformations. Finally, we show how TRPM8 integrates cold and menthol modalities through overlapping but non-identical networks, revealing a coldspot that is central to cold activation of TRPM8 and is the location of allyl isothiocyanate (AITC) binding. These findings enhance our understanding of the molecular basis of physically and chemically induced cool sensation in mammals. Molecular basis for cold and menthol sensing by mammalian TRPM8.,Lee HJ, Park CG, Fedor JG, Peele WA, Borgnia MJ, Lee SY Nat Commun. 2026 Aug 17;17(1):9866. doi: 10.1038/s41467-026-76926-1. PMID:42744822[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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