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,
Jian-Jun Yang,
Ping Hu,
Zhengfeng Xu,
Guoqiang Wan,
Yun Stone Shi
Affiliations
Han Du
State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210032, China; Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210032, China
Chang Ye
State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210032, China; Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210032, China
Dan Wu
State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210032, China; Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210032, China
Yan-Yu Zang
State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210032, China; Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210032, China
Linqing Zhang
Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210032, China
Chen Chen
Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210032, China
Xue-Yan He
Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210032, China
Jian-Jun Yang
Department of Anesthesiology and Perioperative Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, China
Ping Hu
Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Healthcare Hospital, Nanjing 210004, China
Zhengfeng Xu
Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Healthcare Hospital, Nanjing 210004, China
Guoqiang Wan
Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210032, China; Institute for Brain Sciences, Nanjing University, Nanjing 210032, China; Corresponding author
Yun Stone Shi
State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210032, China; Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210032, China; Institute for Brain Sciences, Nanjing University, Nanjing 210032, China; Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210032, China; Corresponding author
Summary: Hypotonic stress causes the activation of swelling-activated nonselective cation channels (NSCCs), which leads to Ca2+-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 Ca2+ influx, which activates Ca2+-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 Ca2+-dependent RVD.
