Two-state model explaining thermodynamic regulation of thermo-gating channels

Temperature-sensitive ion channels, such as those from the TRP family (thermo-TRPs) present in all animal cells, serve to perceive heat and cold sensations. A considerable number of protein structures have been reported for these ion channels, providing a solid basis for revealing their structure-function relationship. Previous functional studies suggest that the thermosensing ability of TRP channels is primarily determined by the properties of their cytosolic domain. Despite their importance in sensing and wide interests in the development of suitable therapeutics, the precise mechanisms underlying acute and steep temperature-mediated channel gating remain enigmatic. Here, we propose a model in which the thermo-TRP channels directly sense external temperature through the formation and dissociation of metastable cytoplasmic domains. An open-close bistable system is described in the framework of equilibrium thermodynamics, and the middle-point temperature T½ similar to the V½ parameter for a voltage-gating channel is defined. Based on the relationship between channel opening probability and temperature, we estimate the change in entropy and enthalpy during the conformational change for a typical thermosensitive channel. Our model is able to accurately reproduce the steep activation phase in experimentally determined thermal-channel opening curves, and thus should greatly facilitate future experimental verification.