Discoveries in structure and physiology of mechanically activated ion channels

Abstract

The ability to sense physical forces is conserved across all organisms. Cells convert mechanical stimuli into electrical or chemical signals via mechanically activated ion channels. In recent years, the identification of new families of mechanosensitive ion channels, such as PIEZO and OSCA/ TMEM63 channels, along with surprising insights into well-studied mechanosensitive channels have driven further developments in the mechanotransduction field. Several well-characterized mechanosensory roles such as touch, blood-pressure sensing and hearing are now linked with primary mechanotransducers. Unanticipated roles of mechanical force sensing continue to be uncovered. Furthermore, high-resolution structures representative of nearly every family of mechanically activated channel described so far have underscored their diversity while advancing our understanding of the biophysical mechanisms of pressure sensing. In this Review, we summarize recent discoveries in the physiology and structures of known mechanically activated ion channel families and discuss their implications for understanding the mechanisms of mechanical force sensing.

Mechanotaxis directsPseudomonas aeruginosatwitching motility

“…Beyond bacteria, eukaryotic cells also have the ability to transduce mechanical signals into cellular responses, regulating an array of physiological processes including development, immunity and touch sensation 33 . Eukaryotic cell motility is also sensitive to mechanical cues.…”

“An intrinsically disordered intracellular domain of PIEZO2 is required for force-from-filament activation of the channel”

“…Two gating models -the force-from-lipids and the force-from-filament model -are commonly used to explain how mechanical forces exerted on a cell are transmitted to mechanically-gated ion channels embedded in the plasma membrane. The force-fromlipids model proposes that mechanical stimuli cause changes in the transbilayer pressure profile, which supposedly lead to conformational changes and thus activation of the channel, whereas the force-from-filament model suggests that mechanical forces are transmitted to the channel by the cytoskeleton either via direct interactions of via intracellular tethers 31,33 . While it was convincingly demonstrated that PIEZO1 is activated by force-from-lipids under experimental conditions in which the cytoskeleton is either completely missing (e.g.…”

“…Most researchers in the field, however, favor an alternative explanation and proposed that the cytoskeleton indirectly transmits forces to the channel by generating local membrane tension via interactions with other membrane proteins, such that the ultimate stimulus that activates PIEZOs is force-from-lipids (Fig. 5l) 3,15,[31][32][33] . Accordingly, this hypothesis implies that a channel with normal force-from-lipids sensitivity would also respond normal to membrane indentation in cells with an intact cytoskeleton.…”

“…Two paradigms are commonly used to explain mechanical force-induced channel activation. The force-from-lipids model proposes that mechanically-induced membrane tension causes changes in the transbilayer pressure profile asymmetry, which leads to conformational changes and thus activation of PIEZOs [31][32][33] . While there is compelling evidence that PIEZO1 is activated by force-from-lipids under experimental conditions where the cytoskeleton is completely missing (e.g.…”

“…force-from-filament ( Fig. 5l) [31][32][33] . The former hypothesis implies that a channel that is normally sensitive to membrane stretch, should also be normally sensitive to membrane indentation in cells with an intact cytoskeleton and that poking-evoked currents of such a channel should be inhibited by disruption of the cytoskeleton.…”