Definition of two agonist types at the mammalian cold-activated channel TRPM8

• Published in: eLife Vol. 5
• Main Authors: Janssens, Annelies, Gees, Maarten, Toth, Balazs Istvan, Ghosh, Debapriya, Mulier, Marie, Vennekens, Rudi, Vriens, Joris, Talavera, Karel, Voets, Thomas
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 23.07.2016; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Agonists (Biochemistry); Allyl isothiocyanate; Animals; Biophysics and Structural Biology; Calcium Signaling; Calcium signalling; Channel gating; Chemical stimuli; Experiments; Ion channels; Isothiocyanate; Isothiocyanates - metabolism; Kinetics; Laboratories; ligand-gated ion channels; Ligands; Menthol; Menthol - metabolism; Mice; Neurons; Neuroscience; Patch-Clamp Techniques; Physiological aspects; Structure-function relationships; Transient receptor potential proteins; TRP channels; TRPM Cation Channels - agonists; TRPM Cation Channels - metabolism; mouse; ligand-gated ion channels; neuroscience; structural biology; biophysics; human; TRP channels; ion channels
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.17240

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.