Proposed gating mechanism and activation process of OSCA/TMEM63 mechanically gated ion channels. Schematic depicting conformational transitions between closed and activated states of OSCA/TMEM63s during mechanical force transduction. (A) Extracellular domains of OSCA/TMEM63s, TM3a–Loop34–TM4a, and TM5a–Loop56, putatively sense the alteration in membrane thickness and stabilize the open conformation; intracellular amphipathic helices linked via a membrane-anchored loop, IL2H2 and IL2H3, possibly act as the sensors for membrane tension, coordinating movements of the transmembrane helix TM6. (B) Expanded and contracted homodimer conformations under closed and open states with asymmetric activation of protomers in OSCA channels. Open-state conformation of OSCA/TMEM63 proteins revealed a proteo-lipidic conducting pore.