Science: How to trigger cold sensations in mammals

According to a new study, cryo-electron microscopy (cryo-EM) reveals how cold-sensitive ion channels are activated in mice, inducing a feeling
of frost caused by cooling compounds such as menthol, which is common in peppermint plants.

Mammals perceive cold
by dropping in temperature or by being exposed to specific compounds.
The basis of this chemically induced cold sensation is mediated by the transient receptor potential melatonin inhibitor 8 (TRPM8) ion channel
.
These channels are expressed in sensory neurons and are the main mechanism
of cold sensation in humans.
However, the molecular basis of cooling agonist activation channels is unclear
.

Previous structural studies have mostly been confined to avian TRPM8, which, despite their similar sequences, exhibit different thermal and chemical sensitivities compared to mammalian TRPM8 and cannot be fully opened
in structural experiments.
However, these studies suggest that membrane signaling phosphatidylinositol-4,5-bisphosphate lipid phospholipid (PIP2) plays an important role
in TRPM8 channel opening.

Understanding the structural basis of human TRPM8 activation can enhance the therapeutic potential
of this cold-sensing pathway for neuroinflammatory diseases and pain management.
By using a coolant combination that does not induce desensitization, Ying Yin and colleagues captured cryo-electron microscopy snapshots
of mouse TRPM8 structures in closed, intermediate, and open states on ligand and lipid-dependent gated pathways.
Yin et al.
revealed the molecular mechanism
of PIP2 and cooling agonist-mediated TRPM8 activation by visualizing the structure of TRPM8 channel gating when opened.
According to the authors, the molecules that produce cold sensations are achieved by hijacking this receptor, while changes in the pores and gates of the channels are consistent with ion conduction and are supported
by electrophysiology and molecular dynamics experiments.