Abstract
Piezo ion channels are sensors of mechanical forces and mediate a wide range of physiological mechanotransduction processes. More than a decade of intense research has elucidated much of the structural and mechanistic principles underlying Piezo gating and its roles in physiology, although wide gaps of knowledge continue to exist. Here, we review the forces and energies involved in mechanical activation of Piezo ion channels and their functional modulation by other chemical and physical stimuli including lipids, voltage, and temperature. We compare the three predominant mechanisms likely to explain Piezo activation-the force-from-lipids mechanism, the tether model, and the membrane footprint theory. Additional sections shine light on how Piezo ion channels may affect each other through spatial clustering and functional cooperativity, and how substantial functional heterogeneity of Piezo ion channels arises as a byproduct of the precise physical environment each channel experiences. Finally, our review concludes by pointing out major research questions and technological limitations that future research can address.