ROCK-dependent and ROCK-independent control of cochlear outer hair cell electromotility.
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.
Zhang
Ming
M
Gonda Department of Cell and Molecular Biology, House Ear Institute, Los Angeles, California 90057, USA.
Kalinec
Gilda M
GM
Urrutia
Raul
R
Billadeau
Daniel D
DD
Kalinec
Federico
F
D000109:Acetylcholine / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D018072:Hair Cells, Auditory, Outer / Q000502:physiology*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D054460:rho-Associated Kinases; D000099291:Adducins
D000109:Acetylcholine; D000577:Amides; D002148:Calmodulin-Binding Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D054460:rho-Associated Kinases; D000099291:Adducins; C108830:Y 27632