Mechanosensitive TMEM63 Ion Channels: Structure, Gating Mechanism, and Emerging Physiological and Pathological Roles

The TMEM63 family of mechanosensitive ion channels has recently emerged as a distinct group of mammalian force sensors evolutionarily related to plant OSCA channels. Structural and functional studies establish TMEM63s as monomeric, high-threshold mechanotransducers featuring an extended IL2 domain, a hydrophobic latch at the membrane interface, and a lateral lipid-accessible pore that may enable both ion conduction and lipid scrambling. These features define a unique gating mechanism, distinct from other mechanosensitive ion channels. Growing genetic and animal evidence indicates that TMEM63s play diverse and essential roles in the nervous system and other tissues, where altered mechanotransduction can lead to severe neurological and systemic dysfunctions. In this review, we summarize recent progress in the structure, gating mechanisms, and physiological functions of TMEM63 channels, with an emphasis on their force-sensing elements, lipid scrambling activities, and implications in human diseases. We also outline future directions for understanding how TMEM63s convert physical forces into biological signals in health and disease.