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J. Biol. Chem., Vol. 283, Issue 33, 22473-22481, August 15, 2008

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Membrane Composition Modulates Prestin-associated Charge Movement^*

John Sfondouris¹, Lavanya Rajagopalan², Fred A. Pereira^¶, and William E. Brownell³

From the Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, ^¶Huffington Center on Aging and Department of Molecular and Cellular Biology, and Keck Center for Interdisciplinary Bioscience Training, Baylor College of Medicine, Houston, Texas 77030

The lateral membrane of the cochlear outer hair cell (OHC) is the site of a membrane-based motor that powers OHC electromotility, enabling amplification and fine-tuning of auditory signals. The OHC membrane protein prestin plays a central role in this process. We have previously shown that membrane cholesterol modulates the peak voltage of prestin-associated nonlinear capacitance in vivo and in vitro. The present study explores the effects of membrane cholesterol and docosahexaenoic acid content on the peak and magnitude of prestin-associated charge movement in a human embryonic kidney (HEK 293) cell model. Increasing membrane cholesterol results in a hyperpolarizing shift in the peak voltage of the nonlinear capacitance (V_pkc) and a decrease in the total charge movement. Both measures depend linearly on membrane cholesterol concentration. Incubation of cholesterol-loaded cells in cholesterol-free media partially restores the V_pkc toward normal values but does not have a compensatory effect on the total charge movement. Decreasing membrane cholesterol results in a depolarizing shift in V_pkc that is restored toward normal values upon incubation in cholesterol-free media. However, cholesterol depletion does not alter the magnitude of charge movement. In contrast, increasing membrane docosahexaenoic acid results in a hyperpolarizing shift in V_pkc that is accompanied by an increase in total charge movement. Our results quantify the relation between membrane cholesterol concentration and prestin-associated charge movement and enhance our understanding of how membrane composition modulates prestin function.

Received for publication, May 15, 2008 , and in revised form, June 19, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 DC00354 (NIDCD; to W. E. B. and F. A. P.). This work was also supported by NSF Grant BES-0522862 (to F. A. P.) and by the Deafness Research Foundation (to L. R.). 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.

¹ Supported by National Institutes of Health Grant T32 DC007367 from NIDCD.

² Supported by a Keck Center for Interdisciplinary Bioscience training grant.

³ To whom correspondence should be addressed: Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-8540; Fax: 713-798-8540; E-mail: brownell{at}bcm.edu.

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