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J. Biol. Chem., Vol. 282, Issue 50, 36659-36670, December 14, 2007

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Tuning of the Outer Hair Cell Motor by Membrane Cholesterol^*

Lavanya Rajagopalan¹², Jennifer N. Greeson^¶3, Anping Xia, Haiying Liu^||, Angela Sturm, Robert M. Raphael^¶4, Amy L. Davidson^**2, John S. Oghalai^¶5, Fred A. Pereira^¶||, and William E. Brownell^¶6

From the Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Department of Neuroscience, and ^||Huffington Center on Aging and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, W. M. Keck Center for Interdisciplinary Bioscience Training, Houston, Texas 77005, the ^¶Department of Bioengineering, Rice University, Houston, Texas 77005, and the ^**Department of Chemistry, Purdue University, West Lafayette, Indiana 47907

Cholesterol affects diverse biological processes, in many cases by modulating the function of integral membrane proteins. We observed that alterations of cochlear cholesterol modulate hearing in mice. Mammalian hearing is powered by outer hair cell (OHC) electromotility, a membrane-based motor mechanism that resides in the OHC lateral wall. We show that membrane cholesterol decreases during maturation of OHCs. To study the effects of cholesterol on hearing at the molecular level, we altered cholesterol levels in the OHC wall, which contains the membrane protein prestin. We show a dynamic and reversible relationship between membrane cholesterol levels and voltage dependence of prestin-associated charge movement in both OHCs and prestin-transfected HEK 293 cells. Cholesterol levels also modulate the distribution of prestin within plasma membrane microdomains and affect prestin self-association in HEK 293 cells. These findings indicate that alterations in membrane cholesterol affect prestin function and functionally tune the outer hair cell.

Received for publication, June 20, 2007 , and in revised form, September 28, 2007.

^* This work was supported in part by NIDCD Grant DC00354 from the National Institutes of Health (to W. E. B. and F. A. P.), National Science Foundation Grant BES-0522862 (to F. A. P.), NIDCD Grant DC008134 from the National Institutes of Health (to R. M. R. and F. A. P.), and 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and Figs. 1-4.

¹ Supported by a Keck Center for Interdisciplinary Bioscience training grant.

² Supported by a Welch Foundation award.

³ Supported by National Institutes of Health NRSA Predoctoral Fellowship DC07563-01.

⁴ Supported by National Science Grants BES-0449379 and NSF BES-0321275.

⁵ Supported by NIDCD Grant DC006671 from the National Institutes of Health.

⁶ To whom correspondence should be addressed: Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-8540; Fax: 713-798-8553; E-mail: brownell{at}bcm.tmc.edu.

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