TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells

Wei Xiong; Nicolas Grillet; Heather M. Elledge; Thomas F.J. Wagner; Bo Zhao; Kenneth R. Johnson; Piotr Kazmierczak; Ulrich Müller

doi:10.1016/j.cell.2012.10.041

TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells

Wei Xiong
, Nicolas Grillet
, Heather M. Elledge
, Thomas F.J. Wagner
, Bo Zhao
, Kenneth R. Johnson
, Piotr Kazmierczak
, Ulrich Müller

Otolaryngology

Producción científica: Article › revisión exhaustiva

213 Citas (Scopus)

Resumen

Hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not known. Here, we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. We conclude that TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.

Idioma original	English
Páginas (desde-hasta)	1283-1295
Número de páginas	13
Publicación	Cell
Volumen	151
N.º	6
DOI	https://doi.org/10.1016/j.cell.2012.10.041
Estado	Published - dic 7 2012

Financiación

W.X. carried out the electrophysiological recordings, calcium imaging experiments, and the analysis of protein localization in transfected cells. W.X. and T.F.J.W. developed the electroporation technique. N.G. carried out in situ hybridizations and the analysis of hair cell morphology and tip links by SEM. W.X., N.G., T.F.J.W., and P.K. carried out immunolocalization experiments in hair cells. H.M.E. and B.Z. generated plasmid constructs and carried out coimmunoprecipitation experiments. K.R.J. provided TMHS mutant mice and generated the TMHS antibody. W.X., N.G., T.F.J.W., P.K., and U.M. contributed to the planning of the work. U.M. wrote the manuscript with help from W.X. and N.G. We thank S.W. Webb and S.R. Harkins-Perry for cloning constructs. This work was supported by the NIH (DC005965 and DC007704 to U.M.), the Dorris Neuroscience Center, the Skaggs Institute for Chemical Biology, and the Bundy Foundation (to W.X. and U.M.).

Financiadores	Número del financiador
Bundy Foundation
National Institutes of Health (NIH)	DC007704
National Institute on Deafness and Other Communication Disorders	R01DC005965
Harold L. Dorris Neuroscience Foundation
Skaggs Institute for Chemical Biology, Scripps Research Institute

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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title = "TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells",

abstract = "Hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not known. Here, we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. We conclude that TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.",

author = "Wei Xiong and Nicolas Grillet and Elledge, \{Heather M.\} and Wagner, \{Thomas F.J.\} and Bo Zhao and Johnson, \{Kenneth R.\} and Piotr Kazmierczak and Ulrich M{\"u}ller",

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AU - Xiong, Wei

AU - Grillet, Nicolas

AU - Elledge, Heather M.

AU - Wagner, Thomas F.J.

AU - Zhao, Bo

AU - Johnson, Kenneth R.

AU - Kazmierczak, Piotr

AU - Müller, Ulrich

PY - 2012/12/7

Y1 - 2012/12/7

N2 - Hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not known. Here, we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. We conclude that TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.

AB - Hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not known. Here, we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. We conclude that TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.

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TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells

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