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.
Highlights
Neurons of the somatosensory system act as individually tuned sensory cells that convert specific thermal, mechanical and/or chemical stimuli into electrical signals, which are conveyed to the central nervous system (Vriens et al, 2014)
While there are already numerous natural and synthetic agonists known for TRPM8 (Almaraz et al, 2014), our results demonstrate that AITC is an atypical agonist, with a mode of action that is fundamentally different from that of all other known TRPM8-activating stimuli
Activation of TRPM8 by cooling or by known agonists such as the natural compounds menthol, thymol and linalool, and the synthetic agonists such as icilin and halothane, is associated with a slowing of the kinetics of voltage-dependent channel gating (Vanden Abeele et al, 2013; Voets et al, 2004; Voets et al, 2007). This slowing of the gating kinetics can be directly explained by a stabilization of the open channel relative to the transition state, as we illustrated in this work for menthol and elsewhere for cooling (Voets et al, 2004)
Summary
Neurons of the somatosensory system act as individually tuned sensory cells that convert specific thermal, mechanical and/or chemical stimuli into electrical signals, which are conveyed to the central nervous system (Vriens et al, 2014). Several members of the TRP superfamily of cation channels act as polymodal molecular sensors of both temperature, and a variety of endogenous and exogenous chemicals, including a plethora of plant-derived compounds (Clapham, 2003; Tominaga et al., 1998; Voets et al, 2005; Vriens et al, 2014). Chemical activation of TRP channels in nerve endings of trigeminal or dorsal root ganglion neurons is generally believed to underlie typical chemesthetic sensations evoked by such plant-derived substances (Bandell et al, 2007), such as the burning heat evoked by capsaicin (the pungent substance in hot peppers), which acts as a selective agonist of the heat-activated TRPV1 (Caterina et al, 1997), and the cool sensation evoked by menthol (the cooling compound in mint plants), due to activation of the cold sensor. We studied the agonist effects of AITC, known as mustard oil, a pungent organosulphur compound derived from Brassica plants. AITC is responsible for the characteristic oral sensations that one experiences upon eating Dijon mustard or wasabi, which contain between
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