| Structural highlights
Function
TRPM8_HUMAN 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 agonist 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. In prostate cancer cells, shows strong inward rectification and high calcium selectivity in contrast to its behavior in normal cells which is characterized by outward rectification and poor cationic selectivity. Plays a role in prostate cancer cell migration (PubMed:25559186). Isoform 2 and isoform 3 negatively regulate menthol- and cold-induced channel activity by stabilizing the closed state of the channel.[1] [2] [3] [4]
Publication Abstract from PubMed
TRPM8 is a non-selective cation channel permeable to both monovalent and divalent cations that is activated by multiple factors, such as temperature, voltage, pressure, and changes in osmolality. It is a therapeutic target for anticancer drug development, and its modulators can be utilized for several pathological conditions. Here, we present a cryo-electron microscopy structure of a human TRPM8 channel in the closed state that was solved at 2.7 A resolution. Our structure comprises the most complete model of the N-terminal pre-melastatin homology region. We also visualized several lipids that are bound by the protein and modeled how the human channel interacts with icilin. Analyses of pore helices in available TRPM structures showed that all these structures can be grouped into different closed, desensitized and open state conformations based on the register of the pore helix S6 which positions particular amino acid residues at the channel constriction.
Structure of human TRPM8 channel.,Palchevskyi S, Czarnocki-Cieciura M, Vistoli G, Gervasoni S, Nowak E, Beccari AR, Nowotny M, Talarico C Commun Biol. 2023 Oct 19;6(1):1065. doi: 10.1038/s42003-023-05425-6. PMID:37857704[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, Nilius B. The principle of temperature-dependent gating in cold channels. Nature. 2004 Aug 12;430(7001):748-54. PMID:15306801 doi:10.1038/nature02732
- ↑ Thebault S, Lemonnier L, Bidaux G, Flourakis M, Bavencoffe A, Gordienko D, Roudbaraki M, Delcourt P, Panchin Y, Shuba Y, Skryma R, Prevarskaya N. Novel role of cold/menthol-sensitive transient receptor potential melastatine family member 8 (TRPM8) in the activation of store-operated channels in LNCaP human prostate cancer epithelial cells. J Biol Chem. 2005 Nov 25;280(47):39423-35. PMID:16174775 doi:10.1074/jbc.M503544200
- ↑ Bidaux G, Beck B, Zholos A, Gordienko D, Lemonnier L, Flourakis M, Roudbaraki M, Borowiec AS, Fernández J, Delcourt P, Lepage G, Shuba Y, Skryma R, Prevarskaya N. Regulation of activity of transient receptor potential melastatin 8 (TRPM8) channel by its short isoforms. J Biol Chem. 2012 Jan 27;287(5):2948-62. PMID:22128173 doi:10.1074/jbc.M111.270256
- ↑ Gkika D, Lemonnier L, Shapovalov G, Gordienko D, Poux C, Bernardini M, Bokhobza A, Bidaux G, Degerny C, Verreman K, Guarmit B, Benahmed M, de Launoit Y, Bindels RJ, Fiorio Pla A, Prevarskaya N. TRP channel-associated factors are a novel protein family that regulates TRPM8 trafficking and activity. J Cell Biol. 2015 Jan 5;208(1):89-107. PMID:25559186 doi:10.1083/jcb.201402076
- ↑ Palchevskyi S, Czarnocki-Cieciura M, Vistoli G, Gervasoni S, Nowak E, Beccari AR, Nowotny M, Talarico C. Structure of human TRPM8 channel. Commun Biol. 2023 Oct 19;6(1):1065. PMID:37857704 doi:10.1038/s42003-023-05425-6
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