Plasticity in Membrane Cholesterol Contributes toward Electrical Maturation of Hearing

Levic, Snezana; Yamoah, Ebenezer N.

doi:10.1074/jbc.m110.186486

Cited by 14 publications

(11 citation statements)

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“…Interestingly, the cholesterol content of the OHC membrane is developmentally regulated, decreasing with maturation [34]. The developmental influence of cholesterol content extends to delayed rectifier potassium channels in afferently innervated hair cells of the chick [20]. Increased Kv currents following cholesterol depletion eliminated spontaneous action potentials, potentially disrupting the transition to a graded receptor potential [20].…”

Section: Discussionmentioning

confidence: 99%

“…Kv currents play a specialized role in hair cell development, repolarizing the spontaneous action potentials (SAPs) credited with directing the tonotopic organization of the auditory periphery [18], [19]. Cholesterol depletion with MβCD potentiates Kv currents in developing auditory hair cells and abolishes SAPs [20]. Kir currents display sensitivity to cholesterol depletion in a variety of cell types, but the role of cholesterol in modulating Kir in auditory hair cells is unknown[2].…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol Influences Voltage-Gated Calcium Channels and BK-Type Potassium Channels in Auditory Hair Cells

et al. 2011

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The influence of membrane cholesterol content on a variety of ion channel conductances in numerous cell models has been shown, but studies exploring its role in auditory hair cell physiology are scarce. Recent evidence shows that cholesterol depletion affects outer hair cell electromotility and the voltage-gated potassium currents underlying tall hair cell development, but the effects of cholesterol on the major ionic currents governing auditory hair cell excitabilityare unknown. We investigated the effects of a cholesterol-depleting agent (methyl beta cyclodextrin, MβCD) on ion channels necessary for the early stages of sound processing. Large-conductance BK-type potassium channels underlie temporal processing and open in a voltage- and calcium-dependent manner. Voltage-gated calcium channels (VGCCs) are responsible for calcium-dependent exocytosis and synaptic transmission to the auditory nerve. Our results demonstrate that cholesterol depletion reduced peak steady-state calcium-sensitive (BK-type) potassiumcurrent by 50% in chick cochlear hair cells. In contrast, MβCD treatment increased peak inward calcium current (∼30%), ruling out loss of calcium channel expression or function as a cause of reduced calcium-sensitive outward current. Changes in maximal conductance indicated a direct impact of cholesterol on channel number or unitary conductance. Immunoblotting following sucrose-gradient ultracentrifugation revealed BK expression in cholesterol-enriched microdomains. Both direct impacts of cholesterol on channel biophysics, as well as channel localization in the membrane, may contribute to the influence of cholesterol on hair cell physiology. Our results reveal a new role for cholesterol in the regulation of auditory calcium and calcium-activated potassium channels and add to the growing evidence that cholesterol is a key determinant in auditory physiology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cholesterol Influences Voltage-Gated Calcium Channels and BK-Type Potassium Channels in Auditory Hair Cells

et al. 2011

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“…These studies have largely relied on the in vitro manipulation of cholesterol using the cyclic oligosaccharide methyl-β-cyclodextrin, whether applied to hair cell preparations or HEK293 cells heterologously expressing hair cell-related proteins. For example, such studies have linked the maturation of hair cell excitability to developmental changes in hair cell cholesterol content [5]. Moreover, in mature hair cells, voltage-gated calcium current is increased while outward potassium current is decreased by cholesterol depletion with methyl-β-cyclodextrin [6].…”

Section: Introductionmentioning

confidence: 99%

Hearing Loss and Hair Cell Death in Mice Given the Cholesterol-Chelating Agent Hydroxypropyl-β-Cyclodextrin

et al. 2012

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Cyclodextrins are sugar compounds that are increasingly finding medicinal uses due to their ability to complex with hydrophobic molecules. One cyclodextrin in particular, 2-hydroxypropyl-β-cyclodextrin (HPβCD), is used as a carrier to solubilize lipophilic drugs and is itself being considered as a therapeutic agent for treatment of Niemann-Pick Type C disease, due to its ability to mobilize cholesterol. Results from toxicological studies suggest that HPβCD is generally safe, but a recent study has found that it causes hearing loss in cats. Whether the hearing loss occurred via death of cochlear hair cells, rendering it permanent, was unexplored. In the present study, we examined peripheral auditory function and cochlear histology in mice after subcutaneous injection of HPβCD to test for hearing loss and correlate any observed auditory deficits with histological findings. On average, auditory brainstem response thresholds were elevated at 4, 16, and 32 kHz in mice one week after treatment with 8,000 mg/kg. In severely affected mice all outer hair cells were missing in the basal half of the cochlea. In many cases, surviving hair cells in the cochlear apex exhibited abnormal punctate distribution of the motor protein prestin, suggesting long term changes to membrane composition and integrity. Mice given a lower dose of 4,000 mg/kg exhibited hearing loss only after repeated doses, but these threshold shifts were temporary. Therefore, cyclodextrin-induced hearing loss was complex, involving cell death and other more subtle influences on cochlear physiology.

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“…Mounting evidence supports a role for cholesterol in the segregation of membrane domains in the cochlea and in modulating cochlear physiology [18, 20, 23, 25, 26]. Until now, such studies have only hinted at the involvement of raft-like, lipid-ordered microdomains that, in other systems, limit lateral diffusion of membrane-associated proteins and aid in the compartmentalization of cell signaling.…”

Section: Discussionmentioning

confidence: 99%

“…While only caveolin and BK-type potassium channels have been biochemically identified in DRMs of cochlea [18], there is growing evidence that cholesterol-enriched microdomains may be involved in a wide range of processes in the inner ear, including sensory transduction[20] and cochlear mechanics [21–24]. Moreover, disruption of these microdomains with cholesterol-chelating cyclodextrins causes aberrant electrophysiological behavior [18, 22, 23, 25, 26], while systemic delivery of cyclodextrins causes profound hearing loss and outer hair cell death with no apparent effect on other systems [27]. …”

Section: Introductionmentioning

confidence: 99%

Localization and proteomic characterization of cholesterol-rich membrane microdomains in the inner ear

Thomas

Cheng

Colby

et al. 2014

Journal of Proteomics

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Biological membranes organize and compartmentalize cell signaling into discrete microdomains, a process that often involves stable, cholesterol-rich platforms that facilitate protein-protein interactions. Polarized cells with distinct apical and basolateral cell processes rely on such compartmentalization to maintain proper function. In the cochlea, a variety of highly polarized sensory and non-sensory cells are responsible for the early stages of sound processing in the ear, yet little is known about the mechanisms that traffic and organize signaling complexes within these cells. We sought to determine the prevalence, localization, and protein composition of cholesterol-rich lipid microdomains in the cochlea. Lipid raft components, including the scaffolding protein caveolin and the ganglioside GM1, were found in sensory, neural, and glial cells. Mass spectrometry of detergent-resistant membrane (DRM) fractions revealed over 600 putative raft proteins associated with subcellular localization, trafficking, and metabolism. Among the DRM constituents were several proteins involved in human forms of deafness including those involved in ion homeostasis, such as the potassium channel KCNQ1, the co-transporter SLC12A2, and gap junction proteins GJA1 and GJB6. The presence of caveolin in the cochlea and the abundance of proteins in cholesterol-rich DRM suggest that lipid microdomains play a significant role in cochlear physiology.

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Plasticity in Membrane Cholesterol Contributes toward Electrical Maturation of Hearing

Cited by 14 publications

References 50 publications

Cholesterol Influences Voltage-Gated Calcium Channels and BK-Type Potassium Channels in Auditory Hair Cells

Cholesterol Influences Voltage-Gated Calcium Channels and BK-Type Potassium Channels in Auditory Hair Cells

Hearing Loss and Hair Cell Death in Mice Given the Cholesterol-Chelating Agent Hydroxypropyl-β-Cyclodextrin

Localization and proteomic characterization of cholesterol-rich membrane microdomains in the inner ear

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