Journal Article

Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel

Hsu, Allen L., Borgnia, Mario J., Yang, Huanghe, Yin, Ying, Le, Son C., Lee, Seok-Yong

2019

Overview

In humans, cold is primarily sensed by transient receptor potential melastatin member 8 (TRPM8), a calcium channel. Yin et al. present cryo–electron microscopy structures of TRPM8 with cooling agents, membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2), and calcium. Structural and functional analyses showed that the PIP2 binding site in TRPM8 is completely different from PIP2 sites in other TRP channels. The binding of PIP2 and cooling agents allosterically enhance each other and activate the channel opening. Thus, the activation mechanism of TRPM8 is distinct from that used by other TRP channels. Science , this issue p. eaav9334 Cryo-EM structures elucidate the molecular basis for cold and menthol sensing and reveal the distinctive PIP2 dependence in the TRPM8 calcium channel. Transient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca 2+ )–permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo–electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP 2 , and Ca 2+ , as well as in complex with the menthol analog WS-12 and PIP 2 . Our structures reveal the binding sites for cooling agonists and PIP 2 in TRPM8. Notably, PIP 2 binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP 2 and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Activation / Allosteric properties / Animals / Binding Sites / Calcium (intracellular) / Calcium - chemistry / Calcium channels / Calcium ions / Calcium permeability / Capsaicin receptors / Channel gating / Channel opening / Cold / Cold Temperature / Conformation / Cooling / Coupling (molecular) / Coupling agents / Cryoelectron Microscopy / Dependence / Detection / Electron microscopy / Interlayers / Intracellular / Ion channels / Ligands / Lipids / Membrane Lipids - chemistry / Membranes / Menthol / Menthol - analogs & derivatives / Menthol - chemistry / Microscopy / Models, Molecular / Organic chemistry / Permeability / Phosphatidylinositol 4,5-diphosphate / Phosphatidylinositol 4,5-Diphosphate - chemistry / Protein Structure, Tertiary / Pyrimidinones - chemistry / Recognition / RESEARCH ARTICLE SUMMARY / Songbirds - physiology / Structural Analysis (Science) / Structural design / Structural engineering / Structure-function relationships / Supercooling / Transient receptor potential proteins / TRPM Cation Channels - chemistry