In Touch With the Mechanosensitive Piezo Channels: Structure, Ion Permeation, and Mechanotransduction

Abstract Mechanotransduction, the conversion of mechanical forces into biological signals, plays critical roles in various physiological and pathophysiological processes in mammals, such as conscious sensing of touch, pain, and sound, as well as unconscious sensing of blood flow-associated shear stress, urine flow, and bladder distention. Among the various molecules involved in mechanotransduction, mechanosensitive (MS) cation channels have long been postulated to represent one critical class of mechanotransducers that directly and rapidly converts mechanical force into electrochemical signals. Despite the awareness of their functional significance, the molecular identities of MS cation channels in mammals had remained elusive for decades till the groundbreaking finding that the Piezo family of genes, including Piezo1 and Piezo2, constitutes their essential components. Since their identification about 6 years ago, tremendous progress has been made in understanding their physiological and pathophysiological importance in mechanotransduction and their structure–function relationships of being the prototypic class of mammalian MS cation channels. On the one hand, Piezo proteins have been demonstrated to serve as physiologically and pathophysiologically important mechanotransducers for most, if not all, mechanotransduction processes. On the other hand, they have been shown to form a remarkable three-bladed, propeller-shaped homotrimeric channel complex comprising a separable ion-conducting pore module and mechanotransduction modules. In this chapter, we review the major advancements, with a particular focus on the structural and biophysical features that enable Piezo proteins to serve as sophisticated MS cation channels for force sensing, transduction, and ion conduction.