The Cation Channel TMEM63B is an Osmosensor Required for Hearing

Abstract

Life has evolved appropriate adaptive responses to maintain cell shape and volume when facing osmotic stress. Hypotonic stress causes the activation of swelling-activated nonselective cation channels (NSCCs), which leads to a Ca2+-dependent regulatory volume decrease (RVD) and the adaptive maintenance of cell volume; however, the molecular identities of the osmosensitive NSCCs remain unclear. Here, we identified TMEM63B as an osmosensitive NSCC activated by hypotonic stress. TMEM63B is enriched in the inner ear sensory hair cells. Genetic deletion of TMEM63B results in necroptosis of outer hair cells (OHCs) and progressive hearing loss. Mechanistically, the TMEM63B channel mediates hypoosmolarity-induced Ca2+ influx, which activates Ca2+-dependent K+ channels required for the maintenance of OHC morphology. These findings demonstrate that TMEM63B is the osmosensor of mammalian ear and the long-sought cation channel mediating Ca2+-dependent RVD.