TMC1 and TMC2 function as the mechano-electrical transduction ion channel in hearing

• Published in: Current opinion in neurobiology Vol. 93; p. 103026
• Main Authors: Deng, Siqi, Yan, Zhiqiang
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2025
• Subjects: Animals; Hair Cells, Auditory - metabolism; Hair Cells, Auditory - physiology; Hearing - physiology; Humans; Ion Channels - metabolism; Mechanotransduction, Cellular - physiology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Proteins - physiology
• ISSN: 0959-4388; 1873-6882; 1873-6882
• DOI: 10.1016/j.conb.2025.103026

Mechanotransduction within the specialized cochlea hair cells is fundamental to perceiving sound waves. This intricate mechanism converts mechanical vibrations into electrical signals that the brain can interpret as sound. The molecular identity of the mechanoelectrical transducer continues to be a subject of intense debate. Transmembrane channel-like protein 1 (TMC1) was initially recognized as a deafness gene in humans, with subsequent studies revealing the hearing loss phenotype in Tmc1 mutant mice. Mechanotransduction currents were lost in the hair cells of Tmc1;Tmc2 double knockout mice, indicating the involvement of TMC1/2 in auditory mechanotransduction. Both TMC1/2 are expressed at the tip of stereocilia in hair cells, the subcellular site of auditory mechanotransduction. Notably, recent in vitro studies have overcome long-standing technical barriers that TMC1/2 are not localized to the cell membrane in heterologous expression and provided compelling evidence that TMC1/2 are mechanically gated ion channels, finally fulfilling both the essential and necessary criteria they must meet as sensory transducers. In hair cells, tip-links possibly relay force to TMC1/2 by tether gating or membrane-tension gating, while the molecular mechanisms underlying each gating mechanism require further investigation. •TMC1 was initially identified as a deafness gene in human; Tmc1 mutant mice exhibit hearing loss phenotypes.•Mechanotransduction currents are fully abolished in the hair cells of Tmc1/2 double knockout mice.•Studies in heterologous system revealed that TMC1/2 are the pore-forming subunits of mechanically gated ion channels.•Tip-links may transmit force to TMC1/2 in hair cells through tether gating or membrane-tension gating mechanisms in synergy.