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The Journal of Neuroscience, April 12, 2006, 26(15):3992-3998; doi:10.1523/JNEUROSCI.4548-05.2006

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Cellular/Molecular
Control of Mammalian Cochlear Amplification by Chloride Anions

Joseph Santos-Sacchi,^1,2,3 Lei Song,¹ Jiefu Zheng,⁴ and Alfred L. Nuttall^4,5

Sections of ¹Otolaryngology, ²Neurobiology, and ³Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, ⁴Oregon Hearing Research Center, Department of Otolaryngology–Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon 97239-3098, and ⁵Kresge Hearing Research Institute, The University of Michigan, Ann Arbor, Michigan 48109-0506

Correspondence should be addressed to Joseph Santos-Sacchi, Otolaryngology, Neurobiology, and Cellular and Molecular Physiology, Yale University School of Medicine, Brandy Memorial Laboratory 246, 333 Cedar Street, New Haven, CT 06510. Email: joseph.santos-sacchi{at}yale.edu

Chloride ions have been hypothesized to interact with the membrane outer hair cell (OHC) motor protein, prestin on its intracellular domain to confer voltage sensitivity (Oliver et al., 2001). Thus, we hypothesized previously that transmembrane chloride movements via the lateral membrane conductance of the cell, G_metL, could serve to underlie cochlear amplification in the mammal. Here, we report on experimental manipulations of chloride-dependent OHC motor activity in vitro and in vivo. In vitro, we focused on the signature electrical characteristic of the motor, the nonlinear capacitance of the cell. Using the well known ototoxicant, salicylate, which competes with the putative anion binding or interaction site of prestin to assess level-dependent interactions of chloride with prestin, we determined that the resting level of chloride in OHCs is near or below 10 mM, whereas perilymphatic levels are known to be 140 mM. With this observation, we sought to determine the effects of perilymphatic chloride level manipulations of basilar membrane amplification in the living guinea pig. By either direct basolateral perfusion of the OHC with altered chloride content perilymphatic solutions or by the use of tributyltin, a chloride ionophore, we found alterations in OHC electromechanical activity and cochlear amplification, which are fully reversible. Because these anionic manipulations do not impact on the cation selective stereociliary process or the endolymphatic potential, our data lend additional support to the argument that prestin activity dominates the process of mammalian cochlear amplification.

Key words: chloride; hearing; outer hair cell; capacitance; basilar membrane; cochlea

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Received Oct. 24, 2005; revised March 1, 2006; accepted March 3, 2006.

Correspondence should be addressed to Joseph Santos-Sacchi, Otolaryngology, Neurobiology, and Cellular and Molecular Physiology, Yale University School of Medicine, Brandy Memorial Laboratory 246, 333 Cedar Street, New Haven, CT 06510. Email: joseph.santos-sacchi{at}yale.edu

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