title: Definition of two agonist types at the mammalian cold-activated channel TRPM8.
abstract: Various TRP channels act as polymodal sensors of thermal and chemical stimuli, but the mechanisms whereby chemical ligands impact on TRP channel gating are poorly understood. Here we show that AITC (allyl isothiocyanate; mustard oil) and menthol represent two distinct types of ligands at the mammalian cold sensor TRPM8. Kinetic analysis of channel gating revealed that AITC acts by destabilizing the closed channel, whereas menthol stabilizes the open channel, relative to the transition state. Based on these differences, we classify agonists as either type I (menthol-like) or type II (AITC-like), and provide a kinetic model that faithfully reproduces their differential effects. We further demonstrate that type I and type II agonists have a distinct impact on TRPM8 currents and TRPM8-mediated calcium signals in excitable cells. These findings provide a theoretical framework for understanding the differential actions of TRP channel ligands, with important ramifications for TRP channel structure-function analysis and pharmacology.
authors.affiliation: Laboratory of Ion Channel Research and TRP channel Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Janssens
authors.affiliation: Laboratory of Ion Channel Research and TRP channel Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Gees
authors.affiliation: Laboratory of Ion Channel Research and TRP channel Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Balazs Istvan
authors.initials: BI
authors.lastname: Toth
authors.affiliation: Laboratory of Ion Channel Research and TRP channel Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Debapriya
authors.initials: D
authors.lastname: Ghosh
authors.affiliation: Laboratory of Ion Channel Research and TRP channel Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Marie
authors.initials: M
authors.lastname: Mulier
authors.affiliation: Laboratory of Ion Channel Research and TRP channel Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.affiliation: Laboratory of Ion Channel Research and TRP channel Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.|Laboratory of Experimental Gynaecology, University of Leuven, Leuven, Belgium.
authors.forename: Joris
authors.initials: J
authors.lastname: Vriens
authors.affiliation: Laboratory of Ion Channel Research and TRP channel Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Talavera
authors.affiliation: Laboratory of Ion Channel Research and TRP channel Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.identifier: 0000-0001-5526-5821
authors.initials: T
authors.lastname: Voets
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D017879:Isothiocyanates / Q000378:metabolism*; D007700:Kinetics; D008610:Menthol / Q000378:metabolism*; D051379:Mice; D018408:Patch-Clamp Techniques; D050053:TRPM Cation Channels / Q000819:agonists* / Q000378:metabolism*
chemical_list: D017879:Isothiocyanates; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D008610:Menthol; C004471:allyl isothiocyanate
keywords: TRP channels; biophysics; human; ion channels; ligand-gated ion channels; mouse; neuroscience; structural biology