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PreprintCited by 30Hearing, Cochlea, Tinnitus, GeneticsIon channel regulation and functionIon Channels and Receptors

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Mechanical gating of the auditory transduction channel TMC1 involves the fourth and sixth transmembrane helices

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Akyuz, Nurunisa, Karavitaki, K. Domenica, Pan, Bifeng, Tamvakologos, Panos I., Brock, Kelly P., Li, Yaqiao, Marks, Debora S., Corey, David P.·2022·Science Advances
DOI 10.1101/2021.12.30.474567PMC PMC9278870

Preprint — published as 10.1126/sciadv.abo1126

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Abstract

The trans m embrane c hannel-like (TMC) 1 and 2 proteins play a central role in auditory transduction, forming ion channels that convert sound into electrical signals. However, the molecular mechanism of their gating remains unknown. Here, using predicted structural models as a guide, we probed the effects of twelve mutations on the mechanical gating of the transduction currents in native hair cells of Tmc1/2 -null mice expressing virally introduced TMC1 variants. Whole-cell electrophysiological recordings revealed that mutations within the pore-lining transmembrane (TM) helices 4 and 6 modified gating, reducing the force sensitivity or shifting the open probability of the channels, or both. For some of the mutants, these changes were accompanied by a change in single-channel conductance. Our observations are in line with a model wherein conformational changes in the TM4 and TM6 helices are involved in the mechanical gating of the transduction channel.

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Metadata

Authors
Akyuz, N., Karavitaki, K. D., Pan, B., Tamvakologos, P. I., Brock, K. P., Li, Y., Marks, D. S., & Corey, D. P.
Affiliations
Harvard University (US)
Corresponding author
Akyuz, Nurunisa
ORCID
Venue
Science Advances
Publisher
openRxiv
Published
2022-01-01
Volume
8
Issue
28
Pages
eabo1126-eabo1126
ISSN
2375-2548 (ISSN-L)
DOI
10.1101/2021.12.30.474567
PMC
PMC9278870
OpenAlex
W4285385650
Cited by
30
References
1
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 9 · 2022: 2
FWCI
3.77
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute on Deafness and Other Communication Disorders (R21DC018631, R01DC000304)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
TMC-1, TMC2, auditory transduction, mechanotransduction, transmembrane helices, TM6, hair cells, ion channels, force sensitivity, open probability, single-channel conductance, ion channel mutations

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