Ligand-stereoselective allosteric activation of cold-sensing TRPM8 channels by an H-bonded homochiral menthol dimer with head-to-head or head-to-tail.

Abstract

Both menthol and its analog WS-12 share the same hydrophobic intra-subunit binding pocket between a voltage-sensor-like domain and a TRP domain in a cold-sensing TRPM8 channel. However, unlike WS-12, menthol upregulates TRPM8 with a low efficacy but a high coefficient of a dose response at membrane hyperpolarization and with ligand stereoselectivity at membrane depolarization. The underlying mechanisms are unknown. Here, this in silico research suggested that the ligand-stereoselective sequential cooperativity between two menthol molecules in the WS-12 pocket is required for allosteric activation of TRPM8. Furthermore, two H-bonded homochiral menthol dimers with both head-to-head and head-to-tail can compete for the WS-12 site via non-covalent interactions. Although both dimers can form an H-bonding network with a voltage sensor S4 to disrupt a S3-S4 salt bridge in the voltage-sensor-like domain to release a "parking brake," only one dimer may drive channel opening by pushing a "gas pedal" in the TRP domain away from the S6 gate against S4. In this way, the efficacy is decreased, but the cooperativity is increased for the menthol effect at membrane hyperpolarization. Therefore, this review may extend a new pathway for ligand-stereoselective allosteric regulation of other voltage- and ligand-gated ion channels by menthol.