{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRPM8 serves as the principal molecular sensor for environmental cold—being activated by cool temperatures and cooling agents such as menthol—and is essential for mediating cold detection, thermosensation, and pain modulation in primary sensory neurons. Studies in wild‐type and genetically modified mice reveal that ablation or mutation of TRPM8 dramatically diminishes cold‐evoked cellular responses, behavioral avoidance to cool surfaces, and cold‐induced analgesia. These findings support the concept of a labeled line for cool sensation wherein TRPM8‐expressing neurons detect both innocuous and noxious cold stimuli."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its sensory role, TRPM8 modulates diverse physiological processes in non‐neuronal tissues. Its activation influences intracellular Ca²⁺ dynamics that are critical for cell survival in prostate epithelial cells, regulates basal tear secretion through corneal cold receptors, and promotes thermogenesis in brown adipose tissue—thereby affecting energy balance and vascular function. TRPM8‐mediated signaling also impacts sperm function, modulates the release of neuropeptides during inflammatory responses in the colon, and underlies the potent analgesic effects seen with menthol application."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, TRPM8’s function is dynamically regulated by post‐translational modifications, the lipid microenvironment, and interactions with accessory proteins. Biophysical studies demonstrate that alterations in N‐glycosylation and lipid raft composition shift TRPM8’s activation thresholds and voltage dependence, while associated factors such as TRP channel–associated proteins and Pirt further fine‐tune its sensitivity to cooling and chemical ligands. 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