Two Distinct Modes of Action of TRPM8 Agonists

Abstract

TRPM8, a transient receptor potential (TRP) cation channel expressed in sensory neurons, functions both as a cold sensor and as an ionotropic receptor for various natural and synthetic ligands, including menthol, eucalyptol, icilin and mustard oil (AITC). The mechanisms whereby TRPM8 agonists act on the channel are incompletely understood. Here we analyzed in detail the changes in kinetics of TRPM8 gating induced by different ligands, and identified two clearly distinct modes of agonist action. The majority of agonists (type I), including menthol, cause a prominent slowing of the channel relaxation kinetics in response to voltage steps, whereas AITC (type II) causes a clear acceleration. These results can be reproduced using a Monod-Wyman-Changeux model, where each subunit can bind a single ligand. In this model, type I agonists cause an stabilization of the open state, while type II ligands destabilize the closed state. These results indicate that agonists can exert energetically distinct effects on the TRPM8 channel protein, and suggest that “equipotent” concentrations of type I and type II agonists may differentially affect electrical activity in sensory neurons.