The force-from-lipid (FFL) principle states that it is the lateral stretch force from the lipid membrane that ultimately opens mechanosensitive (MS) channels, not the external tether nor the internal cytoskeleton. Piezo channels for certain touch or proprioception and the hair-cell channels for hearing or balance apparently obey this principle, which is based on the idea that the lipid bilayer is an amphipathic compartment with a distinct internal force-distribution profile. Physical stretch or insertion of chemical impurities alters this profile, driving channel shape change to conform to the new environment. Thus, FFL governs all dynamic proteins embedded in membrane, including Kv's and TRPs. This article retraces the humble origin of the FFL concept. Paramecium research first created the mind set and the resources to electrically explore other microbial membranes. Patch clamp revealed MS-channel activities from yeast and E. coli spheroplasts. Despite formidable obstacles against interdisciplinary research, the E. coli MS-channel protein, MscL, was purified through fractionation by following its activity, much like enzyme purification. Reconstituted into a simple lipid bilayer, pure MscL retains mechanosensitivity, thus firmly establishing the FFL principle in 1994. The relatively simple MscL and its functional cousin MscS soon became ideal models for detailed analyses. Like the DNA-RNA-protein 'central dogma' or ATP synthesis, FFL is a fundamental principle, which appeared early in evolution, retained in all cellular life forms, and is expected to contribute to future molecular research on sensations, homeostasis, and embryonic development.
Keywords: Mechanosensitive channels; MscL; MscS; lipid force; liposomes; piezo1; piezo2.