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Originally published In Press as doi:10.1074/jbc.M004917200 on June 21, 2000

J. Biol. Chem., Vol. 275, Issue 36, 28000-28005, September 8, 2000
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Rho GTPases Mediate the Regulation of Cochlear Outer Hair Cell Motility by Acetylcholine*

Federico KalinecDagger §, Ming ZhangDagger , Raul Urrutia||, and Gilda KalinecDagger

From the Dagger  Department of Cell and Molecular Biology, House Ear Institute, Los Angeles, California 90057 and  GI Research Unit and Departments of Molecular Neurosciences, Biochemistry and Molecular Biology, and Tumor Biology, Mayo Clinic, Rochester, Minnesota 55905

Outer hair cells are the mechanical effectors of the cochlear amplifier, an active process that improves the sensitivity and frequency discrimination of the mammalian ear. In vivo, the gain of the cochlear amplifier is regulated by the efferent neurotransmitter acetylcholine through the modulation of outer hair cell motility. Little is known, however, regarding the molecular mechanisms activated by acetylcholine. In this study, intracellular signaling pathways involving the small GTPases RhoA, Rac1, and Cdc42 have been identified as regulators of outer hair cell motility. Changes in cell length (slow motility) and in the amplitude of electrically induced movement (fast motility) were measured in isolated outer hair cells patch clamped in whole-cell mode, internally perfused through the patch pipette with different inhibitors and activators of these small GTPases while being externally stimulated with acetylcholine. We found that acetylcholine induces outer hair cell shortening and a simultaneous increase in the amplitude of fast motility through Rac1 and Cdc42 activation. In contrast, a RhoA- and Rac1-mediated signaling pathway induces outer hair cell elongation and decreases fast motility amplitude. These two opposing processes provide the basis for a regulatory mechanism of outer hair cell motility.


* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: House Ear Inst., 2100 West Third St., Los Angeles, CA 90057. Tel.: 213-353-7030; Fax: 213-273-8088; E-mail: fkalinec@hei.org.

|| Supported by the National Institutes of Health Grant DK52913.


Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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