The Cation Channel TMEM63B Is an Osmosensor Required for Hearing

Area of Science:

• Cell Biology
• Otolaryngology
• Molecular Physiology

Background:

• Hypotonic stress activates swelling-activated nonselective cation channels (NSCCs) for cell volume regulation.
• The molecular identity of these osmosensitive NSCCs, crucial for regulatory volume decrease (RVD), remains elusive.
• Inner ear sensory hair cells rely on precise volume control for function.

Purpose of the Study:

• To identify the molecular components of osmosensitive NSCCs involved in cell volume regulation.
• To investigate the role of TMEM63B in the mammalian inner ear and its function in hypotonic stress response.
• To elucidate the mechanism by which TMEM63B contributes to hair cell survival and hearing.

Main Methods:

• Utilized molecular biology techniques to identify TMEM63B as an osmosensitive channel.
• Investigated TMEM63B expression patterns in the inner ear, specifically in outer hair cells (OHCs).
• Performed genetic deletion studies in mice to assess the physiological consequences of TMEM63B loss.

Main Results:

• TMEM63B was identified as an osmosensitive NSCC activated by hypotonic stress.
• TMEM63B is highly expressed in inner ear sensory hair cells.
• Genetic deletion of TMEM63B led to outer hair cell necroptosis and progressive hearing loss.
• TMEM63B mediates calcium influx essential for activating calcium-dependent potassium channels, maintaining OHC morphology.

Conclusions:

• TMEM63B functions as a critical osmosensor in the mammalian inner ear.
• TMEM63B is the long-sought cation channel responsible for calcium-dependent regulatory volume decrease.
• Dysfunction of TMEM63B underlies hearing loss through outer hair cell degeneration.