Mechanically gated OSCA/TMEM63 ion channels: From physiological function to structural basis

The OSCA/TMEM63 family constitutes the largest identified group of mechanically gated ion channels, having pivotal roles in cellular mechanotransduction. OSCAs are osmosensitive and mechanically gated ion channels in plants, while their animal homologs TMEM63s similarly respond to mechanical stimuli and osmotic stress, characterized by smaller conductance and higher mechanoactivation thresholds. Structural studies suggest a conserved "force-from-lipid" gating mechanism for the OSCA/TMEM63 family, in which membrane tension or lipid bilayer curvature directly induces conformational changes and ion conductance. This review summarizes the physiological and pathological roles of OSCA/TMEM63 proteins, highlighting potential molecular mechanisms for their roles in mechanotransduction. Based on the structural homology and functional properties in biological membranes, we proposed a mechanically gated ion channel superfamily comprising OSCA/TMEM63 and TMC proteins.