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J. Biol. Chem., Vol. 282, Issue 5, 3312-3324, February 2, 2007

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Cochlear Function in Mice Lacking the BK Channel , 1, or 4 Subunits^*

Sonja J. Pyott¹, Andrea L. Meredith, Anthony A. Fodor^¶, Ana E. Vázquez^||, Ebenezer N. Yamoah^||, and Richard W. Aldrich^**

From the Department of Otolaryngology Head and Neck Surgery, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205, the Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, the ^¶Department of Bioinformatics/Computer Science, University of North Carolina, Charlotte, North Carolina 28233, the ^||Center for Neuroscience, Department of Otolaryngology, University of California, Davis, California 95616-8635, and the ^**Section of Neurobiology, University of Texas, Austin, Texas 78712

Large conductance voltage- and calcium-activated potassium (BK) channels are important for regulating many essential cellular functions, from neuronal action potential shape and firing rate to smooth muscle contractility. In amphibians, reptiles, and birds, BK channels mediate the intrinsic frequency tuning of the cochlear hair cell by an electrical resonance mechanism. In contrast, inner hair cells of the mammalian cochlea are extrinsically tuned by accessory structures of the cochlea. Nevertheless, BK channels are present in inner hair cells and encode a fast activating outward current. To understand the role of the BK channel and subunits in mammalian inner hair cells, we analyzed the morphology, physiology, and function of these cells from mice lacking the BK channel (Slo^-/-) and also the 1 and 4 subunits (1/4^-/-). 1/4^-/- mice showed normal subcellular localization, developmental acquisition, and expression of BK channels. 1/4^-/- mice showed normal cochlear function as indicated by normal auditory brainstem responses and distortion product otoacoustic emissions. Slo^-/- mice also showed normal cochlear function despite the absence of the BK subunit and the absence of fast activating outward current from the inner hair cells. Moreover, microarray analyses revealed no compensatory changes in transcripts encoding ion channels or transporters in the cochlea from Slo^-/- mice. Slo^-/- mice did, however, show increased resistance to noise-induced hearing loss. These findings reveal the fundamentally different contribution of BK channels to nonmammalian and mammalian hearing and suggest that BK channels should be considered a target in the prevention of noise-induced hearing loss.

Received for publication, September 11, 2006 , and in revised form, November 21, 2006.

^* This work was supported by National Institutes of Health Grants DC07592 and DC03828 (to E. N. Y.), a National Science Foundation graduate research fellowship (to S. J. P.), and the Mathers Foundation (to R. W. A.). 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 Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Otolaryngology Head and Neck Surgery, Johns Hopkins School of Medicine, 720 Rutland Ave., Traylor 521, Baltimore, MD 21205. Tel.: 410-955-3877; Fax: 410-614-4748; E-mail: spyott{at}jhmi.edu.

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