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J. Biol. Chem., Vol. 275, Issue 36, 28000-28005, September 8, 2000
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From the 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.
Rho GTPases Mediate the Regulation of Cochlear Outer Hair Cell
Motility by Acetylcholine*
§,
,
, and
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
*
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.
Supported by the National Institutes of Health Grant DK52913.
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