Cooperativity of K _v 7.4 channels confers ultrafast electromechanical sensitivity and emergent properties in cochlear outer hair cells

Abstract

The mammalian cochlea relies on active electromotility of outer hair cells (OHCs) to resolve sound frequencies. OHCs use ionic channels and somatic electromotility to achieve the process. It is unclear, though, how the kinetics of voltage-gated ionic channels operate to overcome extrinsic viscous drag on OHCs at high frequency. Here, we report ultrafast electromechanical gating of clustered Kv7.4 in OHCs. Increases in kinetics and sensitivity resulting from cooperativity among clustered-Kv7.4 were revealed, using optogenetics strategies. Upon clustering, the half-activation voltage shifted negative, and the speed of activation increased relative to solitary channels. Clustering also rendered Kv7.4 channels mechanically sensitive, confirmed in consolidated Kv7.4 channels at the base of OHCs. Kv7.4 clusters provide OHCs with ultrafast electromechanical channel gating, varying in magnitude and speed along the cochlea axis. Ultrafast Kv7.4 gating provides OHCs with a feedback mechanism that enables the cochlea to overcome viscous drag and resolve sounds at auditory frequencies.

The cochlear outer hair cell speed paradox

“…Power tuning curves in Fig. 3 D and E partially account for the OHC electrical corner frequency by driving the cell with a low-pass-filtered voltage, but no attempt was made to address the influence of MET kinetics ( 39 ), ion channel gating and expression ( 9 , 10 ), prestin expression ( 31 ), hair bundle electromotility ( 40 ), inhomogeneous expression and deformation, or mechanical forces associated with the traveling wave. The present OHC model is minimalistic, and reduces a complex cell with inhomogeneous expression and properties into a single lumped element, yet is sufficient to resolve the OHC speed paradox.…”

“…The RC corner is unusually high in OHCs owing to a standing K + conductance in the membrane ( 9 ). Ultrafast K + channel gating might also play a role in extending the effective RC ( 10 ). Evidence that OHCs can modulate voltage at auditory frequencies is compelling, but whether or not the motor mechanism can be driven by voltage cycle-by-cycle is less clear.…”

State dependent effects on the frequency response of prestin’s real and imaginary components of nonlinear capacitance

“…Additionally, we previously modelled initial voltage influences on NLC as resulting from OHC molecular motor-motor (prestin) interactions 33 . For Kv 7.4 channels, cooperativity has been found to impart mechanical sensitivity to the channel in OHCs 61 . Another possibility is the presence of a conductive element influencing the interaction between voltage sensor charge and the membrane field, where that element alters with tension.…”

Intrinsic mechanical sensitivity of auditory neurons as a contributor to sound-driven neural activity

“…Recent reports have shown that besides voltage-dependence, outward K + channels such as Kv1.1/1.2 and Kv7 are modulated by mechanical stimuli (Hao et al, 2013;Perez-Flores et al, 2020), whereby the channel's voltage sensitivity is enhanced (Long et al, 2005). Kv1 and Kv7 channels are members of the cadre of outward K + channels that dominates the type I afferent AN membrane (Lv et al, 2010;Mo et al, 2002;Wang et al, 2013).…”