Structures of a mammalian TRPM8 in closed state

Transient receptor potential melastatin 8 (TRPM8) channel is a Ca2+-permeable non-selective cation channel that acts as the primary cold sensor in humans. TRPM8 is also activated by ligands such as menthol, icilin, and phosphatidylinositol 4,5-bisphosphate (PIP2), and desensitized by Ca2+. Here we have determined electron cryo-microscopy structures of mouse TRPM8 in the absence of ligand, and in the presence of Ca2+ and icilin at 2.5-3.2 angstrom resolution. The ligand-free state TRPM8 structure represents the full-length structure of mammalian TRPM8 channels with a canonical S4-S5 linker and the clearly resolved selectivity filter and outer pore loop. TRPM8 has a short but wide selectivity filter which may account for its permeability to hydrated Ca2+. Ca2+ and icilin bind in the cytosolic-facing cavity of the voltage-sensing-like domain of TRPM8 but induce little conformational change. All the ligand-bound TRPM8 structures adopt the same closed conformation as the ligand-free structure. This study reveals the overall architecture of mouse TRPM8 and the structural basis for its ligand recognition. The mechanism of cold-activated TRPM8 channel activation remains unclear. Here, authors have determined structures of mouse TRPM8 in apo or ligand-bound states, providing insights into the activation of TRPM8 structures in different states.

Automated summary

The TRPM8 channel acts as the primary cold sensor in humans and can be activated by ligands such as menthol, icilin, and PIP2. This study determined the structures of mouse TRPM8 in different states, revealing its overall architecture and the basis for ligand recognition.