Structural basis for promiscuous action of monoterpenes on TRP channels

Thi Hong Dung Nguyen,Makoto Tominaga,Hisashi Okumura,Satoru G. Itoh

doi:10.1038/s42003-021-01776-0

Abstract

Monoterpenes are major constituents of plant-derived essential oils and have long been widely used for therapeutic and cosmetic applications. The monoterpenes menthol and camphor are agonists or antagonists for several TRP channels such as TRPM8, TRPV1, TRPV3 and TRPA1. However, which regions within TRPV1 and TRPV3 confer sensitivity to monoterpenes or other synthesized chemicals such as 2-APB are unclear. In this study we identified conserved arginine and glycine residues in the linker between S4 and S5 that are related to the action of these chemicals and validated these findings in molecular dynamics simulations. The involvement of these amino acids differed between TRPV3 and TRPV1 for chemical-induced and heat-evoked activation. These findings provide the basis for characterization of physiological function and biophysical properties of ion channels.

Highlights

Monoterpenes are major constituents of plant-derived essential oils and have long been widely used for therapeutic and cosmetic applications
We focused mainly on the shared residues in the S4–S5 linker domain since the glycine residue in TRP melastatin 8 (TRPM8) corresponding to G573 in mTRPV3 is not known to be part of the menthol-binding site and the S4–S5 linker is known to have broad involvement in several functions of thermosensitive transient receptor potential (TRP) channels
Investigation of the actions of monoterpene agonists on TRP vanilloid 3 (TRPV3) will provide clues to clarify the structural basis of activation, which could lead to increased understanding of the role of TRPV3 in physiological function and in disease

Summary

Introduction

Monoterpenes are major constituents of plant-derived essential oils and have long been widely used for therapeutic and cosmetic applications. In this study we identified conserved arginine and glycine residues in the linker between S4 and S5 that are related to the action of these chemicals and validated these findings in molecular dynamics simulations The involvement of these amino acids differed between TRPV3 and TRPV1 for chemical-induced and heat-evoked activation. Members of the TRP ion channel family play important roles as polymodal sensors to detect and respond to changes in temperature, pH, voltage, osmolarity, and exogenous molecules involved in taste, smell, and pheromone responses[1]. Whereas many TRPV subfamily members act as heat sensors, the TRPM8 channel is known to be involved in sensation induced by cool temperatures (

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