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The conductance and organization of the TMC1-containing mechanotransducer channel complex in auditory hair cells.

The conductance and organization of the TMC1-containing mechanotransducer channel complex in auditory hair cells. Thumbnail


Abstract

Transmembrane channel-like protein 1 (TMC1) is thought to form the ion-conducting pore of the mechanoelectrical transducer (MET) channel in auditory hair cells. Using single-channel analysis and ionic permeability measurements, we characterized six missense mutations in the purported pore region of mouse TMC1. All mutations reduced the Ca2+ permeability of the MET channel, triggering hair cell apoptosis and deafness. In addition, Tmc1 p.E520Q and Tmc1 p.D528N reduced channel conductance, whereas Tmc1 p.W554L and Tmc1 p.D569N lowered channel expression without affecting the conductance. Tmc1 p.M412K and Tmc1 p.T416K reduced only the Ca2+ permeability. The consequences of these mutations endorse TMC1 as the pore of the MET channel. The accessory subunits, LHFPL5 and TMIE, are thought to be involved in targeting TMC1 to the tips of the stereocilia. We found sufficient expression of TMC1 in outer hair cells of Lhfpl5 and Tmie knockout mice to determine the properties of the channels, which could still be gated by hair bundle displacement. Single-channel conductance was unaffected in Lhfpl5-/- but was reduced in Tmie-/-, implying TMIE very likely contributes to the pore. Both the working range and half-saturation point of the residual MET current in Lhfpl5-/- were substantially increased, suggesting that LHFPL5 is part of the mechanical coupling between the tip-link and the MET channel. Based on counts of numbers of stereocilia per bundle, we estimate that each PCDH15 and LHFPL5 monomer may contact two channels irrespective of location.

Journal Article Type Article
Acceptance Date Aug 30, 2022
Online Publication Date Oct 3, 2022
Publication Date Oct 11, 2022
Publicly Available Date Mar 29, 2024
Journal Proceedings of the National Academy of Sciences
Print ISSN 0027-8424
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 119
Issue 41
Article Number e2210849119
DOI https://doi.org/10.1073/pnas.2210849119
Keywords Multidisciplinary
Publisher URL https://www.pnas.org/doi/full/10.1073/pnas.2210849119

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