The force-from-lipid (FFL) principle of mechanosensitivity, at large and in elements

Focus on touch and hearing distracts attention from numerous subconscious force sensors, such as the vital control of blood pressure and systemic osmolarity, and sensors in nonanimals. Multifarious manifestations should not obscure invariant and fundamental physicochemical principles. We advocate that force from lipid (FFL) is one such principle. It is based on the fact that the self-assembled bilayer necessitates inherent forces that are large and anisotropic, even at life's origin. Functional response of membrane proteins is governed by bilayer force changes. Added stress can redirect these forces, leading to geometric changes of embedded proteins such as ion channels. The FFL principle was first demonstrated when purified bacterial mechanosensitive channel of large conductance (MscL) remained mechanosensitive (MS) after reconstituting into bilayers. This key experiment has recently been unequivocally replicated with two vertebrate MS K2p channels. Even the canonical Kv and the Drosophila canonical transient receptor potentials (TRPCs) have now been shown to be MS in biophysical and in physiological contexts, supporting the universality of the FFL paradigm. We also review the deterministic role of mechanical force during stem cell differentiation as well as the cell-cell and cell-matrix tethers that provide force communications. In both the ear hair cell and the worm's touch neuron, deleting the cadherin or microtubule tethers reduces but does not eliminate MS channel activities. We found no evidence to distinguish whether these tethers directly pull on the channel protein or a surrounding lipid platform. Regardless of the implementation, pulling tether tenses up the bilayer. Membrane tenting is directly visible at the apexes of the stereocilia.