Molecular mechanism of menthol-induced TRPV5 channel inhibition

Abstract TRPV5 channels play a critical role in calcium homeostasis and are implicated in various pathophysiological conditions. Here, we demonstrate that the monoterpene menthol, commonly used for pain and inflammation management, is an inhibitor of TRPV5. Electrophysiology experiments reveal that menthol blocks ion conduction through a slow blocker mechanism. Using single-particle cryo-EM, we determine the structure of menthol-bound TRPV5, which shows menthol interacting with W583, a residue previously implicated in channel permeation, gating and binding of endogenous modulators. These findings expand the repertoire of TRPV5 modulators and suggest that menthol could serve as a scaffold for developing channel-targeting modulators.