{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRPM8 is a calcium‐permeable ion channel specialized for detecting cool to cold temperatures and chemical cooling agents such as menthol and icilin. Biophysical studies demonstrate that its temperature sensitivity is intimately coupled to voltage‐dependent gating, with cold shifting its activation curves and large conformational changes underlying its opening. Notably, pharmacological modulation via protein kinase A can shift its gating properties, and unlike some other TRP channels, TRPM8 does not exhibit pore dilation upon prolonged activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classic role in sensory neurons, TRPM8 is widely expressed in non‐neuronal tissues and several cancers, where its localization and function appear context dependent. In the prostate, for instance, TRPM8 expression is tightly regulated by androgens—with mature secretory epithelial cells displaying robust plasma membrane expression, while less‐differentiated cells lose this pattern—and its activation by natural agonists such as prostate‐specific antigen and testosterone triggers Ca²⁺ influx associated with apoptotic signals and reduced cell migration. Similarly, TRPM8 has been implicated in modulating vascular tone, where its stimulation can induce either vasoconstriction or vasodilation depending on the pre‐existing smooth muscle state, and in lung epithelial cells and keratinocytes where variant forms localize to the endoplasmic reticulum to govern intracellular calcium homeostasis, inflammatory cytokine release, mitochondrial function, and cellular differentiation. In several cancers—including melanoma, glioblastoma, pancreatic adenocarcinoma, and oral squamous cell carcinoma—TRPM8 expression correlates with altered proliferation and migration, suggesting a multifaceted role in tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, the normal function of TRPM8 depends on its precise structural assembly and interaction with regulatory factors. Recent work has shown that TRPM8 subunits oligomerize via a C‐terminal coiled–coil domain, a process essential for generating functional channels, while the channel forms a stable complex with polyphosphate and associated molecules—interactions that are critical for channel gating. In parallel, the development of highly potent and selective synthetic agonists (such as novel carboxamides) has expanded our ability to modulate TRPM8 activity, offering promising leads for therapeutic intervention aimed at conditions like cold hypersensitivity and cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Thomas Voets, Guy Droogmans, Ulrich Wissenbach, et al. 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