Stiffness and tension gradients of the hair cell’s tip-link complex in the mammalian cochlea

Tobin, Mélanie; Chaiyasitdhi, Atitheb; Michel, Vincent; Michalski, Nicolas; Martin, Pascal

doi:10.7554/elife.43473

Cited by 55 publications

(92 citation statements)

References 99 publications

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“…Unfolding of MADs in PCDH15 and CDH23 (28) could explain uncompromised hair-cell mechanotransduction under extreme stimuli that would require large tip-link extensibility (∼100 nm) (65,66). These results highlight the potential complexities of the tip-link mechanical response and provide a structural framework to both compare and interpret complementary experimental results (26,27,59,64,(67)(68)(69) and to understand the function of PCDH15 as a key component of the tip links that open inner-ear transduction channels (SI Appendix, Note 4).…”

Section: Discussionmentioning

confidence: 83%

Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception

Choudhary

Narui

Neel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The vertebrate inner ear, responsible for hearing and balance, is able to sense minute mechanical stimuli originating from an extraordinarily broad range of sound frequencies and intensities or from head movements. Integral to these processes is the tip-link protein complex, which conveys force to open the inner-ear transduction channels that mediate sensory perception. Protocadherin-15 and cadherin-23, two atypically large cadherins with 11 and 27 extracellular cadherin (EC) repeats, are involved in deafness and balance disorders and assemble as parallel homodimers that interact to form the tip link. Here we report the X-ray crystal structure of a protocadherin-15 + cadherin-23 heterotetrameric complex at 2.9-Å resolution, depicting a parallel homodimer of protocadherin-15 EC1-3 molecules forming an antiparallel complex with two cadherin-23 EC1-2 molecules. In addition, we report structures for 10 protocadherin-15 fragments used to build complete high-resolution models of the monomeric protocadherin-15 ectodomain. Molecular dynamics simulations and validated crystal contacts are used to propose models for the complete extracellular protocadherin-15 parallel homodimer and the tip-link bond. Steered molecular dynamics simulations of these models suggest conditions in which a structurally diverse and multimodal protocadherin-15 ectodomain can act as a stiff or soft gating spring. These results reveal the structural determinants of tip-link–mediated inner-ear sensory perception and elucidate protocadherin-15’s structural and adhesive properties relevant in disease.

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Section: Discussionmentioning

confidence: 83%

Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception

Choudhary

Narui

Neel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…A filamentous tip link connects adjacent rows of stereocilia and is responsible for gating mechano-electric transduction (MET) channels. At rest, the tip link is under constant tension (1). This tension contributes substantially to the total stiffness of the hair bundle and establishes the resting open probability of the MET channel, which has a role in the high sensitivity of the auditory and vestibular systems.…”

Section: Introductionmentioning

confidence: 99%

Decades-old model of slow adaptation in sensory hair cells is not supported in mammals

2020

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Hair cells detect sound and motion through a mechano-electric transduction (MET) process mediated by tip links connecting shorter stereocilia to adjacent taller stereocilia. Adaptation is a key feature of MET that regulates a cell’s dynamic range and frequency selectivity. A decades-old hypothesis proposes that slow adaptation requires myosin motors to modulate the tip-link position on taller stereocilia. This “motor model” depended on data suggesting that the receptor current decay had a time course similar to that of hair-bundle creep (a continued movement in the direction of a step-like force stimulus). Using cochlear and vestibular hair cells of mice, rats, and gerbils, we assessed how modulating adaptation affected hair-bundle creep. Our results are consistent with slow adaptation requiring myosin motors. However, the hair-bundle creep and slow adaptation were uncorrelated, challenging a critical piece of evidence upholding the motor model. Considering these data, we propose a revised model of hair cell adaptation.

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“…3, using the parameter values of Table S2. These values have been chosen to correspond to those measured in a recent biophysical study of mammalian cochlear hair cells (41), in which all the parameters relevant to this work have been estimated from the same data set. The open probability curve P p ðXÞ is plotted in red, with the origin of the X axis set such that the hair bundle sits at X ¼ 0 when no external force is applied.…”

Section: Open Probability Curvesmentioning

confidence: 99%

The Development of Cooperative Channels Explains the Maturation of Hair Cell'S Mechanotransduction

Gianoli

Risler

Kozlov

2020

Biophysical Journal

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Hearing relies on the conversion of mechanical stimuli into electrical signals. In vertebrates, this process of mechanoelectrical transduction (MET) is performed by specialized receptors of the inner ear, the hair cells. Each hair cell is crowned by a hair bundle, a cluster of microvilli that pivot in response to sound vibrations, causing the opening and closing of mechanosensitive ion channels. Mechanical forces are projected onto the channels by molecular springs called tip links. Each tip link is thought to connect to a small number of MET channels that gate cooperatively and operate as a single transduction unit. Pushing the hair bundle in the excitatory direction opens the channels, after which they rapidly reclose in a process called fast adaptation. It has been experimentally observed that the hair cell's biophysical properties mature gradually during postnatal development: the maximal transduction current increases, sensitivity sharpens, transduction occurs at smaller hairbundle displacements, and adaptation becomes faster. Similar observations have been reported during tip-link regeneration after acoustic damage. Moreover, when measured at intermediate developmental stages, the kinetics of fast adaptation varies in a given cell, depending on the magnitude of the imposed displacement. The mechanisms underlying these seemingly disparate observations have so far remained elusive. Here, we show that these phenomena can all be explained by the progressive addition of MET channels of constant properties, which populate the hair bundle first as isolated entities and then progressively as clusters of more sensitive, cooperative MET channels. As the proposed mechanism relies on the difference in biophysical properties between isolated and clustered channels, this work highlights the importance of cooperative interactions between mechanosensitive ion channels for hearing.

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Stiffness and tension gradients of the hair cell’s tip-link complex in the mammalian cochlea

Cited by 55 publications

References 99 publications

Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception

Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception

Decades-old model of slow adaptation in sensory hair cells is not supported in mammals

The Development of Cooperative Channels Explains the Maturation of Hair Cell'S Mechanotransduction

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