PIEZO channels as multimodal mechanotransducers

All living beings experience a wide range of endogenous and exogenous mechanical forces. The ability to detect these forces and rapidly convert them into specific biological signals is essential to a wide range of physiological processes. In vertebrates, these fundamental tasks are predominantly achieved by two related mechanosensitive ion channels called PIEZO1 and PIEZO2. PIEZO channels are thought to sense mechanical forces through flexible transmembrane blade-like domains. Structural studies indeed show that these mechanosensory domains adopt a curved conformation in a resting membrane but become flattened in a membrane under tension, promoting an open state. Yet, recent studies suggest the intriguing possibility that distinct mechanical stimuli activate PIEZO channels through discrete molecular rearrangements of these domains. In addition, biological signals downstream of PIEZO channel activation vary as a function of the mechanical stimulus and of the cellular context. These unique features could explain how PIEZOs confer cells the ability to differentially interpret a complex landscape of mechanical cues.