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J. Biol. Chem., Vol. 278, Issue 37, 35644-35650, September 12, 2003

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ROCK-dependent and ROCK-independent Control of Cochlear Outer Hair Cell Electromotility^*

Ming Zhang   ¶, Gilda M. Kalinec  ¶, Raul Urrutia || **, Daniel D. Billadeau || and Federico Kalinec   

From the Gonda Department of Cell and Molecular Biology, House Ear Institute, Los Angeles, California 90057, the Departments of Otolaryngology and Cell and Neurobiology, University of Southern California, Los Angeles, California 90033, the Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, and the ^||Division of Developmental Oncology Research and the Departments of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905

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.

Received for publication, February 17, 2003 , and in revised form, June 27, 2003.

^* This work was supported in part by NIDCD Grants DC05220 (to F. K.) and DC05335 (to G. M. K.) from the National Institutes of Health and by a grant from the S. Mark Taper Foundation (to G. M. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Both authors contributed equally to this work.

^** Supported by National Institutes of Health Grants DK52913 and DK56620 and by the Lustgarten Foundation.

To whom correspondence should be addressed: Dept. of Cell and Molecular Biology, House Ear Inst., 2100 West Third St., Los Angeles, CA 90057. Tel.: 213-353-7030; Fax: 213-273-8088; E-mail: fkalinec{at}hei.org.

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