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How Your Body Senses Cold—And Why Menthol Feels Cool

Researchers used cryo‑electron microscopy to capture multiple conformational states of the cold‑sensing ion channel TRPM8 as it transitions from closed to open. The study revealed that actual cold and menthol trigger the channel through overlapping yet distinct allosteric pathways, with cold acting on the pore region and menthol binding elsewhere. Combined cold and menthol produce a synergistic opening, enabling the first structural view of the fully open channel. The findings have medical relevance, informing therapies such as the TRPM8‑activating eye drop Acoltremon and potential treatments for pain, migraines, and dry eye.