TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells

Bo Zhao; Zizhen Wu; Nicolas Grillet; Linxuan Yan; Wei Xiong; Sarah Harkins-Perry; Ulrich Müller

doi:10.1016/j.neuron.2014.10.041

TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells

Bo Zhao
, Zizhen Wu
, Nicolas Grillet
, Linxuan Yan
, Wei Xiong
, Sarah Harkins-Perry
, Ulrich Müller

Otolaryngology

Research output: Contribution to journal › Article › peer-review

183 Scopus citations

Abstract

Hair cells are the mechanosensory cells of the inner ear. Mechanotransduction channels in hair cells are gated by tip links. The molecules that connect tip links to transduction channels are not known. Here we show that the transmembrane protein TMIE forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5. Alternative splicing of the PCDH15 cytoplasmic domain regulates formation of this ternary complex. Transducer currents are abolished by a homozygous Tmie-null mutation, and subtle Tmie mutations that disrupt interactions between TMIE and tip links affect transduction, suggesting that TMIE is an essential component of the hair cell's mechanotransduction machinery that functionally couples the tip link to the transduction channel. The multisubunit composition of the transduction complex and the regulation of complex assembly by alternative splicing is likely critical for regulating channel properties in different hair cells and along the cochlea's tonotopic axis.

Original language	English
Pages (from-to)	954-967
Number of pages	14
Journal	Neuron
Volume	84
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2014.10.041
State	Published - Dec 3 2014

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Inc.

Funding

We thank Robert Fettiplace and Maryline Beurg for help with establishing the fluid-jet stimulation system, Andy Groves for Pax2-Cre mice, and Jian Zuo for prestin-CreER T2 mice. This work was funded with support from the NIH (UM DC005965, DC007704), the Dorris Neuroscience Center, the Skaggs Institute for Chemical Biology, and the Bundy Foundation (UM).

Funders	Funder number
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 Neuroscience

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10.1016/j.neuron.2014.10.041

Cite this

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abstract = "Hair cells are the mechanosensory cells of the inner ear. Mechanotransduction channels in hair cells are gated by tip links. The molecules that connect tip links to transduction channels are not known. Here we show that the transmembrane protein TMIE forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5. Alternative splicing of the PCDH15 cytoplasmic domain regulates formation of this ternary complex. Transducer currents are abolished by a homozygous Tmie-null mutation, and subtle Tmie mutations that disrupt interactions between TMIE and tip links affect transduction, suggesting that TMIE is an essential component of the hair cell's mechanotransduction machinery that functionally couples the tip link to the transduction channel. The multisubunit composition of the transduction complex and the regulation of complex assembly by alternative splicing is likely critical for regulating channel properties in different hair cells and along the cochlea's tonotopic axis.",

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AU - Wu, Zizhen

AU - Grillet, Nicolas

AU - Yan, Linxuan

AU - Xiong, Wei

AU - Harkins-Perry, Sarah

AU - Müller, Ulrich

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N2 - Hair cells are the mechanosensory cells of the inner ear. Mechanotransduction channels in hair cells are gated by tip links. The molecules that connect tip links to transduction channels are not known. Here we show that the transmembrane protein TMIE forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5. Alternative splicing of the PCDH15 cytoplasmic domain regulates formation of this ternary complex. Transducer currents are abolished by a homozygous Tmie-null mutation, and subtle Tmie mutations that disrupt interactions between TMIE and tip links affect transduction, suggesting that TMIE is an essential component of the hair cell's mechanotransduction machinery that functionally couples the tip link to the transduction channel. The multisubunit composition of the transduction complex and the regulation of complex assembly by alternative splicing is likely critical for regulating channel properties in different hair cells and along the cochlea's tonotopic axis.

AB - Hair cells are the mechanosensory cells of the inner ear. Mechanotransduction channels in hair cells are gated by tip links. The molecules that connect tip links to transduction channels are not known. Here we show that the transmembrane protein TMIE forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5. Alternative splicing of the PCDH15 cytoplasmic domain regulates formation of this ternary complex. Transducer currents are abolished by a homozygous Tmie-null mutation, and subtle Tmie mutations that disrupt interactions between TMIE and tip links affect transduction, suggesting that TMIE is an essential component of the hair cell's mechanotransduction machinery that functionally couples the tip link to the transduction channel. The multisubunit composition of the transduction complex and the regulation of complex assembly by alternative splicing is likely critical for regulating channel properties in different hair cells and along the cochlea's tonotopic axis.

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TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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