Advances and recent insights into the gating mechanisms of the mechanically activated ion channels PIEZO1 and PIEZO2

PIEZO1 and PIEZO2 are mechanically gated ion channels that confer mechanosensitivity to a variety of cell types and are thus essential for numerous physiological processes, including touch, pain, blood-pressure regulation, cell migration, or immune function. Recently published cryo-electron microscopy structures of PIEZO1 and PIEZO2 have enabled the structure-guided examination of PIEZO channel function, which has significantly improved our understanding of the cellular and molecular mechanisms underlying the mechanogating of PIEZOs. Here, we summarize evidence suggesting that forces acting in and on cells are transmitted to PIEZOs via both membrane tension (force-from-lipids) and by cytoskeletal strain (force-from-filament) and propose that the two force-transmission pathways act in parallel or synergistically to activate PIEZOs. Moreover, we discuss the role of different protein domains in the detection of mechanical forces from different origins and propose that PIEZOs are polymodal mechanosensors that detect different types of mechanical stimuli via different intramolecular force-coupling mechanisms.