Abstract
Outer hair cell electromotility is crucial for the proper function of the cochlear amplifier, the active process that enhances sensitivity and frequency discrimination of the mammalian ear. Previous work (Kalinec, F., Zhang, M., Urrutia, R., and Kalinec, G. (2000) J. Biol. Chem. 275, 28000-28005) has suggested a role for Rho GTPases in the regulation of outer hair cell electromotility, although the signaling pathways mediated by these enzymes remain to be established. Here we have investigated the cellular and molecular mechanisms underlying the homeostatic regulation of the electromotile response of guinea pig outer hair cells. Our findings defined a ROCK-mediated signaling cascade that continuously modulates outer hair cell electromotility by selectively targeting the cytoskeleton. A distinct ROCK-independent pathway functions as a fast resetting mechanism for this system. Neither pathway affects the function of prestin, the unique molecular motor of outer hair cells. These results extend our understanding of a basic mechanism of both normal human hearing and deafness, revealing the key role of the cytoskeleton in the regulation of outer hair cell electromotility and suggesting ROCK as a molecular target for modulating the function of the cochlear amplifier.
Highlights
Basic mechanism of both normal human hearing and outer hair cells (OHCs) must undergo continuous mechanical changes to opdeafness, revealing the key role of the cytoskeleton in timize the sensitivity and frequency selectivity of the cochlea the regulation of outer hair cell electromotility and sug- (10 –13)
Little is known about the nature of the homeostatic control, a strong inhibitory effect on the gain of the cochlear amplifier has been associated with acetylcholine (ACh) released by efferent terminals innervating OHCs (14 –16)
GTPase RhoA and its downstream target ROCK are crucial for the mechanical homeostasis and regulation of the electromotile response of cochlear OHCs
Summary
Basic mechanism of both normal human hearing and OHCs must undergo continuous mechanical changes to opdeafness, revealing the key role of the cytoskeleton in timize the sensitivity and frequency selectivity of the cochlea the regulation of outer hair cell electromotility and sug- (10 –13). The cochlea may be challenged by Cochlear outer hair cells (OHCs) undergo reversible changes in length when electrically stimulated. This electromotile response results from a membrane-based force generator mechanism associated with conformational changes and rearrangement of a voltage-sensitive integral membrane protein [1]. In addition to the homeostatic mechanism of continued regulation, OHCs may require a “reset” switch for fast inhibition of signal amplification to protect the cochlea from sudden bursts of high intensity noise. We show that the cellular mechanism of homeostatic control of OHC electromotility involves Rho-mediated cytoskeletal changes without affecting the pres-
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