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Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing

View ORCID ProfileAngela Ballesteros, Kenton J. Swartz
doi: https://doi.org/10.1101/2021.09.24.461722
Angela Ballesteros
Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892
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  • ORCID record for Angela Ballesteros
  • For correspondence: angela.ballesteros@nih.gov swartzk@ninds.nih.gov
Kenton J. Swartz
Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892
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  • For correspondence: angela.ballesteros@nih.gov swartzk@ninds.nih.gov
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ABSTRACT

The mechanoelectrical transduction (MET) channel complex of auditory hair cells converts sound into electrical signals, allowing us to hear. After decades of research, the transmembrane-like channel 1 and 2 (TMC1 and TMC2) have been recently identified as pore-forming subunits of the MET channels, but the molecular peculiarity that differentiates these two proteins and makes TMC1 essential for hearing remains elusive. Here, we show that TMC1, but not TMC2, is essential for membrane remodeling triggered by a decrease in intracellular calcium concentration. We demonstrate that inhibition of MET channels or buffering of intracellular calcium lead to pronounced phosphatidylserine externalization, membrane blebbing and ectosome release at the hair cell sensory organelle, culminating in the loss of TMC1 protein. Moreover, three TMC1 deafness-causing mutations cause constitutive phosphatidylserine externalization that correlates with the deafness phenotype, suggesting that the mechanisms of hearing loss involve alterations in membrane homeostasis.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted September 25, 2021.
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Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing
Angela Ballesteros, Kenton J. Swartz
bioRxiv 2021.09.24.461722; doi: https://doi.org/10.1101/2021.09.24.461722
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Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing
Angela Ballesteros, Kenton J. Swartz
bioRxiv 2021.09.24.461722; doi: https://doi.org/10.1101/2021.09.24.461722

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