A gating model for the mechanical activation of sensory TRP channels

Transient receptor potential (TRP) channels are notorious for their proposed roles as sensors of chemical, thermal and mechanical stimuli in multiple cell types. While the roles of TRP channels as mechanotransducers in physiological conditions remain debated, it has been proposed that most of them can be activated by mechanical stimulation (Liu and Montell, BBRC, 2015; Startek et al., IJMS, 2019). The main objective of this study was to provide a theoretical framework serving to assess the determinants of TRP channel mechanosensitivity. We hypothesized that the mechanically-induced activation is boosted by the weak voltage dependence of TRP channels, as previously proposed for thermal stimuli and chemical agonists. To test this hypothesis, we examined the properties of an existing close-open gating model, which we extended to consider the influence of an external mechanical stimulus, in addition to the known contribution of temperature and the transmembrane membrane potential. The model predicts that the thermal and mechanical sensitivities are determined by the balance between an energy component associated to the protein volume and another associated to the protein-membrane surface. The model supports the hypothesis linking the mechanical- and voltage-dependent gating by predicting inverse relationships between the mechanical sensitivity and the gating valence. In addition, it explains how TRP channels can act as secondary mechanosensors by being stimulated by second messengers generated upon mechanical activation of signaling pathways. We speculate that, natural selection of ionic channels with low gating change yielded better sensors of thermal, chemical and mechanical stimuli. On the other hand, it may be possible that a TRP channel functioning primarily as thermo- or chemo-sensor is also found to the mechanosensitive in special experimental conditions, by the reason of having a low gating charge, without necessarily having a physiological role as mechanotransducer.