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Updated: Jun 5, 2025

Dextran Labeling and Uptake in Live and Functional Murine Cochlear Hair Cells
Published on: February 8, 2020
Human TMC1 and TMC2 are mechanically gated ion channels
Songdi Fu1, Xueqi Pan2, Mingshun Lu3
1Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, China; Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China.
Transmembrane channel-like proteins 1 and 2 (TMC1/2) are identified as mechanically activated ion channels. This study confirms their function in hair cells, crucial for hearing.
Area of Science:
- Cell Biology
- Neuroscience
- Biophysics
Background:
- Mammalian transmembrane channel-like proteins 1 and 2 (TMC1/2) are candidates for mechanotransduction in hair cells.
- Previous studies lacked evidence of mechanical gating due to TMC1/2 mislocalization in cultured cells.
Purpose of the Study:
- To identify membrane-localized TMC1/2 mutants and demonstrate their mechanical gating in heterologous cells.
- To confirm wild-type human TMC1/2 localization and function in the plasma membrane.
- To investigate the role of TMC1/2 as pore-forming mechanotransduction channels.
Main Methods:
- Domain swapping with OSCA1.1 and point mutations to achieve membrane localization of mouse TMC1/2.
- Whole-genome CRISPRi screening for wild-type human TMC1/2 plasma membrane localization.
- Electrophysiological recordings (whole-cell and single-channel) to assess mechanical gating and ion channel activity.
Main Results:
- Identified membrane-localized mouse TMC1/2 mutants that are mechanically gated.
- Achieved plasma membrane localization of wild-type human TMC1/2, which responded to mechanical stimuli.
- Demonstrated stretch-activated currents and single-channel activity for human TMC1/2.
- Deafness-related TMC1 mutations affected ion channel properties, confirming TMC1/2 as pore-forming channels.
Conclusions:
- Human TMC1/2 are pore-forming, mechanically activated ion channels.
- Provides strong evidence supporting the role of TMC1/2 as essential mechanotransduction channels in auditory hair cells.
- Resolves controversy regarding TMC1/2 function in mechanotransduction.
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