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 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. 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 clusters of channels, whose sensitivity is sharpened by cooperative gating.

Nonextensive realizations in interacting ion channels: Implications for mechano-electrical transducer mechanisms

“…The generalized sigmoid function here reconciles the biomechanical arrangement originally proposed by Gianoli et al with the theoretical premises ( [26,27]). We reason that the generalized Boltzmann equation certainly is an adequate application in IxX adjustments, especially in those cases where there are significant deviations from the empirical analysis and classical distribution ( [32,45]).…”

“…4 and 5) concerning X magnitude. From an experimental point of view, it is known that the sigmoid shape is modulated by z X ( [45,10,27]). This argument for a relationship between z X and non-extensivity converges with the computational study by Xenakis et al, suggesting the non-extensive pore influence in ion channels ( [68,6]).…”

“…Consequently, the system may be classified as a coupled mechanical oscillator. Their biomechanical formulation reproduced the main properties of hair-cell mechanoelectrical transduction ( [26,27]).…”

An inter-channel cooperative mechanism mediates PIEZO1’s exquisite mechanosensitivity

“…Due to their elastic properties, lipid bilayers propagate membrane deformations induced by distinct channel states, promoting nearby channels to adopt similar conformations. In most cases described in the literature, these inter-channel cooperative effects are mediated by a change of membrane thickness resulting from the hydrophobic mismatch between hydrophobic protein domains and surrounding lipids [24][25][26][27][28] . However, membrane thinning and thickening rapidly decay with lateral distance and most of membrane deformation free energy is brought about by the first annulus of lipids in contact with the protein 29 , thus dramatically limiting the spatial range of cooperative effects.…”

Recent advances in cochlear hair cell nanophysiology: subcellular compartmentalization of electrical signaling in compact sensory cells

“…Formation of membrane nanodomains containing distinct subsets of proteins and a close linkage between the actin core of stereocilia and the cell membrane were demonstrated for chick vestibular hair cells 66 . These data showed, for example, that cholesterol was enriched at the tips of stereocilia, where it potentially stiffens the membrane and could function as a force focus for the MET complex 61 , 64 , 69 . Other data also showed that PIP 2 modulates core MET channel properties 13 , 14 , possibly due to direct interaction with TMIE 10 .…”