How cooling chemical compounds trigger cold sensation in mammals

Cryo-electron microscopy (cryo-EM) reveals how cold-sensing ion channels in mice activate to induce the frosty sensation caused by cooling chemical compounds like the menthol commonly found in mint plants, according to a new study. Mammals sense cold through drops in temperature or by exposure to particular chemical compounds. The basis for this chemical-induced cold sensation is mediated by transient receptor potential melastatin 8 (TRPM8) ion channels. These channels are expressed in sensory neurons and function as the primary mechanism for cool sensation in humans. However, the molecular basis for channel activation by cooling agonists has not been clear. Most previous structural studies have been limited to avian TRPM8, which, despite their sequence similarity, exhibit different thermal and chemical sensitivities compared with mammalian TRPM8 and cannot be fully opened during structural experiments. However, these studies have suggested that the membrane signaling lipid phosphatidylinositol-4,5-bisphosphate (PIP₂) plays an important role in TRPM8 channel opening. Understanding the structural basis of TRPM8 activation in humans could enhance the therapeutical potential of this cold-sensing channel for neuroinflammatory diseases and pain management. Using a combination of cooling agents that do not induce desensitization, Ying Yin and colleagues captured cryo-EM snapshots of mouse TRPM8 structures in closed, intermediate and open states along the ligand- and lipid-dependent gating pathway. By visualizing the structure of TRPM8 channel gating as it opens, Yin et al. revealed the molecular mechanism for PIP₂- and cooling agonist-mediated TRPM8 activation. According to the authors, molecules that generate a cold sensation do so by hijacking this receptor and the changes in the pore and gate of the channel are consistent with ion conduction and are supported by electrophysiology and molecular dynamics experiments.