Corns, L.F. orcid.org/0000-0003-1139-3527, Johnson, S.L. orcid.org/0000-0003-3355-650X, Kros, C.J. et al. (1 more author) (2016) Tmc1 Point Mutation Affects Ca2+ Sensitivity and Block by Dihydrostreptomycin of the Mechanoelectrical Transducer Current of Mouse Outer Hair Cells. Journal of Neuroscience, 36 (2). pp. 336-349. ISSN 0270-6474
Abstract
The transduction of sound into electrical signals depends on mechanically sensitive ion channels in the stereociliary bundle. The molecular composition of this mechanoelectrical transducer (MET) channel is not yet known. Transmembrane channel-like protein isoforms 1 (TMC1) and 2 (TMC2) have been proposed to form part of the MET channel, although their exact roles are still unclear. Using Beethoven (Tmc1Bth/Bth) mice, which have an M412K point mutation in TMC1 that adds a positive charge, we found that Ca2+ permeability and conductance of the MET channel of outer hair cells (OHCs) were reduced. Tmc1Bth/Bth OHCs were also less sensitive to block by the permeant MET channel blocker dihydrostreptomycin, whether applied extracellularly or intracellularly. These findings suggest that the amino acid that is mutated in Bth is situated at or near the negatively charged binding site for dihydrostreptomycin within the permeation pore of the channel. We also found that the Ca2+ dependence of the operating range of the MET channel was altered by the M412K mutation. Depolarization did not increase the resting open probability of the MET current of Tmc1Bth/Bth OHCs, whereas raising the intracellular concentration of the Ca2+ chelator BAPTA caused smaller increases in resting open probability in Bth mutant OHCs than in wild-type control cells. We propose that these observations can be explained by the reduced Ca2+ permeability of the mutated MET channel indirectly causing the Ca2+ sensor for adaptation, at or near the intracellular face of the MET channel, to become more sensitive to Ca2+ influx as a compensatory mechanism.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Copyright © 2016 Corns et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
Keywords: | adaptation; calcium; development; hair cell; mechanotransduction; TMC1 |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) |
Funding Information: | Funder Grant number WELLCOME TRUST (THE) 102892/Z/13/Z |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 26 Jul 2017 11:14 |
Last Modified: | 26 Jul 2017 11:18 |
Published Version: | https://doi.org/10.1523/JNEUROSCI.2439-15.2016 |
Status: | Published |
Publisher: | Society for Neuroscience |
Refereed: | Yes |
Identification Number: | 10.1523/JNEUROSCI.2439-15.2016 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:119400 |