TY - JOUR TI - Definition of two agonist types at the mammalian cold-activated channel TRPM8 AU - Janssens, Annelies AU - Gees, Maarten AU - Toth, Balazs Istvan AU - Ghosh, Debapriya AU - Mulier, Marie AU - Vennekens, Rudi AU - Vriens, Joris AU - Talavera, Karel AU - Voets, Thomas A2 - Swartz, Kenton J VL - 5 PY - 2016 DA - 2016/07/23 SP - e17240 C1 - eLife 2016;5:e17240 DO - 10.7554/eLife.17240 UR - https://doi.org/10.7554/eLife.17240 AB - 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. KW - ion channels KW - TRP channels KW - ligand-gated ion channels JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -