Abstract
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 alpha and beta subunits in mammalian inner hair cells, we analyzed the morphology, physiology, and function of these cells from mice lacking the BK channel alpha (Slo-/-) and also the beta1 and beta4 subunits (beta1/4-/-). Beta1/4-/- mice showed normal subcellular localization, developmental acquisition, and expression of BK channels. Beta1/4-/- 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 BKalpha 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.
Highlights
Numerous studies have shown that BK channels are present in inner hair cells (IHCs),2 the subset of hair cells in the mammalian cochlea responsible for transducing sound to the central nervous system
IHCs are extrinsically tuned by accessory structures of the cochlea [9], the BK current found in IHCs does not require external calcium for activation [18, 25, 26], and BK channels in IHCs are extrasynaptic [20]
Inner Hair Cells from SloϪ/Ϫ Mice Do Not Express the BK␣ Subunit and Have Normal Morphology and Synaptic Innervation—Immunostaining with antibodies against the BK channel was performed to confirm the absence of the BK␣ subunit from the IHCs of SloϪ/Ϫ mice
Summary
Generation of Transgenic Mice—SloϪ/Ϫ were generated as described previously [7] and maintained on an inbred FVB/NJ background. Ear canal sound pressure levels, measured by an emissions microphone assembly (ER10Bϩ; Etymotic Research) embedded in the probe, were sampled, synchronously averaged, and processed using a fast Fourier transform for geometric mean (GM) frequencies ((f1 ϫ f2)0.5) ranging from 5.6 to 17.2 kHz (f2 ϭ 6.3–19.2 kHz). Three GM frequencies (17.1, 18.4, and 19.7 kHz) were not included in the average plots shown due to artifacts related to the 1/4-wave cancellation effect in the mouse ear canal, which result in primary tones being more intense than their targeted levels [30]. To compare differences in the expression of channels and transporters between the cochleae of Sloϩ/ϩ and SloϪ/Ϫ mice, transcripts containing the keywords “channels” and “transporters” (ignoring case) in the Annotations in the Mouse430_2.gin file provided by Affymetrix were compared. Box plots are shown with the median line, whisker tops, and bottoms indicating the 90th and 10th percentile and box tops and bottoms indicating the 75th and 25th percentile. p values were calculated using a two-tailed paired or unpaired (as appropriate) t test assuming unequal variances
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