PIEZO1. (A) Proposed model of PIEZO channels based on cryoelectron microscopy imaging.⁴⁹  Gray and tan models represent closed and open channels. Red dashed lines indicate possible ion-conduction pathways. Presumably, force-induced motion (arrows) of the peripheral blade or peripheral helices (PH) leads to conformational arrangement and gating of the channel. Reprinted from Ge et al⁴⁹  with permission. (B) Human PIEZO1 channels with HX-associated mutations display slow inactivation kinetics. HEK293 cells expressing mutant PIEZO1 were stimulated by a series of mechanical steps. Representative traces of mechanically activated inward currents from cells expressing wild-type (WT; red) or mutant (blue) PIEZO1 normalized to peak. Maximum currents from each mutant are overlaid to highlight differences in inactivation kinetics.⁴³  CED, extracellular COOH-terminal domain; CTD, intracellular COOH-terminal domain; IH, inner helix; OH, outer helix.