A Theoretical Framework for Mechanical Gating of Sensory TRP Channels

Several members of the transient receptor potential (TRP) channel superfamily are notorious for been activated by chemical, thermal and mechanical stimuli. Despite the obvious advances resulting from functional studies and structural characterizations, the mechanisms of TRP channel gating remain obscure. Amongst all, the mechanically-induced gating is probably the most intriguing activation mode of these channels. The main objective of this study was to provide a theoretical framework serving to assess the determinants of TRP channel mechanosensitivity. We hypothesized that, as for thermal stimuli and chemical agonists, the mechanically-induced activation is boosted by the weak voltage dependence of TRP channels. To assess this, we extended a gating model that was previously shown to describe the thermal activation of multiple sensory TRP channels, by considering an additional linear free energy term associated to an external mechanical stimulus. The resulting 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 serves to explain how TRP channels can act as secondary mechanosensors by being stimulated by second messengers generated upon mechanical activation of signaling pathways. Finally, we delineate experimentally testable-hypotheses that may result in further understanding of TRP channel mechanosensitivity and discuss the relevance of this property for mechanotransduction.