1.A.4.5.13
TRPM8 of the collared flycatcher of 1103 aas.  It is 83% identical to the human ortholog. Its structure has been determined to ~4.1 Å resolution by cryo EM (Yin et al. 2018). The structure reveals a three-layered architecture. The amino-terminal domain with a fold distinct among known TRP structures, together with the carboxyl-terminal region, forms a large two-layered cytosolic ring that extensively interacts with the transmembrane channel layer. The structure suggests that the menthol-binding site is located within the voltage-sensor-like domain and thus provides a structural glimpse of the design principle of the molecular transducer for cold and menthol sensation (Yin et al. 2018). TrpM8 is the primary cold and menthol receptor in humans.  The structure has been solved for the collared flycatcher at 4.1 Å resolution (6BPQ_A - D (Yin et al. 2017). Transient receptor potential cation channel subfamily M member 8, TrpM8, the primary cold and menthol receptor in humans.  The structure has been solved for the collared flycatcher TrpM8 at 4.1 Å resolution (6BPQ_A - D (Yin et al. 2017). Transient receptor potential cation channel subfamily M member 8, TrpM8 is the primary cold and menthol receptor in humans.  The structure has been solved for the collared flycatcher at 4.1 Å resolution (6BPQ_A - D (Yin et al. 2017). Cold thermoreceptor neurons detect temperature drops with highly sensitive molecular machinery concentrated in their peripheral free nerve endings. The main molecular entity responsible for cold transduction in these neurons is the thermo-TRP channel TRPM8. Cold, cooling compounds such as menthol, voltage, and osmolality rises activate this polymodal ion channel. Dysregulation of TRPM8 activity underlies several physiopathological conditions, including painful cold hypersensitivity in response to axonal damage, migraine, dry-eye disease, an overactive bladder, and several forms of cancer. TRPM8 could be an attractive target for treating these highly prevalent diseases. Different mutagenesis approaches have allowed the identification of specific amino acids in the cavity comprised of the S1-S4 and TRP domains that determine modulation by chemical ligands (Pertusa et al. 2023). Different studies revealing specific regions within the N- and C-termini and the transmembrane domain contribute to cold-dependent TRPM8 gating. Pertusa et al. 2023 highlight the milestones in the field: cryo-EM structures of TRPM8 that have provided a better comprehension of the 21 years of research on this ion channel, shedding light on the molecular bases underlying its modulation, and promoting the future rational design of novel drugs to selectively regulate abnormal TRPM8 activity under pathophysiological conditions (Pertusa et al. 2023).