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

Abstract

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.