The Cation Channel TMEM63B Is an Osmosensor Required for Hearing
Han Du, Chang Ye, Dan Wu, Yan‐Yu Zang, Linqing Zhang, Chen Chen, Xue‐Yan He, Jianjun Yang, Ping Hu, Zhengfeng Xu, Guoqiang Wan, Yun Stone Shi
Abstract
Hypotonic stress causes the activation of swelling-activated nonselective cation channels (NSCCs), which leads to Ca 2+ -dependent regulatory volume decrease (RVD) and adaptive maintenance of the 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 hypo-osmolarity-induced Ca 2+ influx, which activates Ca 2+ -dependent K + channels required for the maintenance of OHC morphology. These findings demonstrate that TMEM63B is an osmosensor of the mammalian inner ear and the long-sought cation channel mediating Ca 2+ -dependent RVD.