The development of cooperative channels explains the maturation of hair cell’s mechanotransduction

Abstract

Hearing relies on the conversion of mechanical stimuli into electrical signals. In vertebrates, this process of mechano-electrical 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 hair-bundle 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, 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. SIGNIFICANCE Hair cells are the sensory receptors of the inner ear that convert mechanical stimuli into electrical signals transmitted to the brain. Sensitivity to mechanical stimuli and the kinetics of mechanotransduction currents change during hair-cell development. The same trend, albeit on a shorter timescale, is also observed during hair-cell recovery from acoustic trauma. Furthermore, the current kinetics in a given hair cell depends on the stimulus magnitude, and the degree of that dependence varies with development. These phenomena have so far remained unexplained. Here, we show that they can all be reproduced using a single unifying mechanism: the progressive formation of channel pairs, in which individual channels interact through the lipid bilayer and gate cooperatively.

Fast adaptation of cooperative channels engenders Hopf bifurcations in auditory hair cells

“…In our previous work, we developed a new gating-spring model with cooperative channels (20) and then used it to explain changes observed in the biophysical properties of hair cells during development and tip-link regeneration (50). In the present study, we developed the model further and show how the mechanotransduction apparatus of a hair cell can not only transduce but also amplify incident sounds at kilohertz frequencies, typical of amniote hearing.…”

Fast adaptation of cooperative channels engenders Hopf bifurcations in auditory hair cells

“…In our previous work, we developed a new gating-spring model with cooperative channels (17) and then used it to explain changes observed in the biophysical properties of hair cells during development and tip-link regeneration (18). In the present paper, we have developed the model further and shown how the mechanotransduction apparatus of a hair cell can not only transduce, but also amplify incident sounds at high frequencies.…”

“…Here, we present a new model of hair-bundle motility that relies on the established electrochemical gradient of Ca 2+ as an energy source to power active oscillations, similarly to what has been proposed by Choe et al, (1998) (9). We base our model on an earlier proposal that each tip link is connected to two channels, the states of which are reciprocally coupled to hair-bundle motion by membrane-mediated forces (17, 18). This model is not limited by the action of myosin motors and can show spontaneous oscillations at high frequencies.…”