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The intermediate C2-state mouse TRPM8 structure in complex with the cooling agonist C3 and PI(4,5)P2
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 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is controlled by cooling compounds together with the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP(2)). Our knowledge of cold sensation and the therapeutic potential of TRPM8 for neuroinflammatory diseases and pain will be enhanced by understanding the structural basis of cooling agonist- and PIP(2)-dependent TRPM8 activation. We present cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP(2)-dependent gating pathway. Our results uncover two discrete agonist sites, state-dependent rearrangements in the gate positions, and a disordered-to-ordered transition of the gate-forming S6-elucidating the molecular basis of chemically induced cool sensation in mammals. Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP(2).,Yin Y, Zhang F, Feng S, Butay KJ, Borgnia MJ, Im W, Lee SY Science. 2022 Oct 14;378(6616):eadd1268. doi: 10.1126/science.add1268. Epub 2022 , Oct 14. PMID:36227998[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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