Format

Send to

Choose Destination
Neuron. 2018 Aug 22;99(4):736-753.e6. doi: 10.1016/j.neuron.2018.07.033.

TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells.

Author information

1
Departments of Otolaryngology and Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
2
Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
3
Molecular Biology and Genetics Section, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
4
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
5
Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: dcorey@hms.harvard.edu.
6
Departments of Otolaryngology and Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: jeffrey.holt@childrens.harvard.edu.

Abstract

The proteins that form the permeation pathway of mechanosensory transduction channels in inner-ear hair cells have not been definitively identified. Genetic, anatomical, and physiological evidence support a role for transmembrane channel-like protein (TMC) 1 in hair cell sensory transduction, yet the molecular function of TMC proteins remains unclear. Here, we provide biochemical evidence suggesting TMC1 assembles as a dimer, along with structural and sequence analyses suggesting similarity to dimeric TMEM16 channels. To identify the pore region of TMC1, we used cysteine mutagenesis and expressed mutant TMC1 in hair cells of Tmc1/2-null mice. Cysteine-modification reagents rapidly and irreversibly altered permeation properties of mechanosensory transduction. We propose that TMC1 is structurally similar to TMEM16 channels and includes ten transmembrane domains with four domains, S4-S7, that line the channel pore. The data provide compelling evidence that TMC1 is a pore-forming component of sensory transduction channels in auditory and vestibular hair cells.

KEYWORDS:

TMC1; TMC2; auditory; balance; hair cell; hearing; mechanosensory transduction; mechanotransduction; sensory transduction; vestibular

PMID:
30138589
PMCID:
PMC6360533
DOI:
10.1016/j.neuron.2018.07.033
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center