Human TMC1 and TMC2 are Mechanically Gated Ion Channels

Abstract

Hearing is an essential sense that enables humans and animals to detect and interpret sounds in the environment, playing a critical role in communication, navigation, foraging, and the awareness of potential dangers. The exact identity of auditory receptors has long been an unresolved question in the field of sensory biology. Transmembrane channel-like proteins 1 and 2 (TMC1 and TMC2, TMC1/2) have been recognized as strong candidates for mechanotransduction ion channels in mammalian hair cells, yet the exact roles remain controversial. The debate centers on the lack of evidence demonstrating that mammalian TMC1/2 are mechanosensitive in cultured cells, primarily due to their failure to heterologously localize to the plasma membrane. Here, through domain swapping with OSCA1.1 and alanine scanning mutagenesis, we successfully found membrane-localized mouse TMC1/2 mutants that exhibit mechanosensitivity in cultured cells. Furthermore, knockdown of the UROD gene, identified via CRISPRi screening, promoted the heterologous expression of human TMC1/2 at the plasma membrane, and revealed that human TMC1/2 function as mechanically activated ion channels. Deafness-associated mutations in human TMC1 altered its reversal potential, indicating that human TMC1/2 are pore-forming subunits of mechanotransduction ion channels. In summary, this study demonstrates that human TMC1 and TMC2 function as pore-forming, mechanically activated ion channels, supporting their essential roles as auditory receptors in hair cells.

Date of Award	2025
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Hyo Keun PARK (Supervisor) & Yu-hsuan Tsai (Supervisor)