Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity.
Aminoglycosides (AG) are commonly prescribed antibiotics with potent bactericidal activities. One main side effect is permanent sensorineural hearing loss, induced by selective inner ear sensory hair cell death. Much work has focused on AG's initiating cell death processes, however, fewer studi...
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doaj-c56add5781904e789a330e2871448d8f2020-11-25T00:23:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0167e2234710.1371/journal.pone.0022347Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity.Abdelrahman AlharaznehLauren LukMarkus HuthAshkan MonfaredPeter S SteygerAlan G ChengAnthony J RicciAminoglycosides (AG) are commonly prescribed antibiotics with potent bactericidal activities. One main side effect is permanent sensorineural hearing loss, induced by selective inner ear sensory hair cell death. Much work has focused on AG's initiating cell death processes, however, fewer studies exist defining mechanisms of AG uptake by hair cells. The current study investigated two proposed mechanisms of AG transport in mammalian hair cells: mechanotransducer (MET) channels and endocytosis. To study these two mechanisms, rat cochlear explants were cultured as whole organs in gentamicin-containing media. Two-photon imaging of Texas Red conjugated gentamicin (GTTR) uptake into live hair cells was rapid and selective. Hypocalcemia, which increases the open probability of MET channels, increased AG entry into hair cells. Three blockers of MET channels (curare, quinine, and amiloride) significantly reduced GTTR uptake, whereas the endocytosis inhibitor concanavalin A did not. Dynosore quenched the fluorescence of GTTR and could not be tested. Pharmacologic blockade of MET channels with curare or quinine, but not concanavalin A or dynosore, prevented hair cell loss when challenged with gentamicin for up to 96 hours. Taken together, data indicate that the patency of MET channels mediated AG entry into hair cells and its toxicity. Results suggest that limiting permeation of AGs through MET channel or preventing their entry into endolymph are potential therapeutic targets for preventing hair cell death and hearing loss.http://europepmc.org/articles/PMC3144223?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Abdelrahman Alharazneh Lauren Luk Markus Huth Ashkan Monfared Peter S Steyger Alan G Cheng Anthony J Ricci |
spellingShingle |
Abdelrahman Alharazneh Lauren Luk Markus Huth Ashkan Monfared Peter S Steyger Alan G Cheng Anthony J Ricci Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. PLoS ONE |
author_facet |
Abdelrahman Alharazneh Lauren Luk Markus Huth Ashkan Monfared Peter S Steyger Alan G Cheng Anthony J Ricci |
author_sort |
Abdelrahman Alharazneh |
title |
Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. |
title_short |
Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. |
title_full |
Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. |
title_fullStr |
Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. |
title_full_unstemmed |
Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. |
title_sort |
functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2011-01-01 |
description |
Aminoglycosides (AG) are commonly prescribed antibiotics with potent bactericidal activities. One main side effect is permanent sensorineural hearing loss, induced by selective inner ear sensory hair cell death. Much work has focused on AG's initiating cell death processes, however, fewer studies exist defining mechanisms of AG uptake by hair cells. The current study investigated two proposed mechanisms of AG transport in mammalian hair cells: mechanotransducer (MET) channels and endocytosis. To study these two mechanisms, rat cochlear explants were cultured as whole organs in gentamicin-containing media. Two-photon imaging of Texas Red conjugated gentamicin (GTTR) uptake into live hair cells was rapid and selective. Hypocalcemia, which increases the open probability of MET channels, increased AG entry into hair cells. Three blockers of MET channels (curare, quinine, and amiloride) significantly reduced GTTR uptake, whereas the endocytosis inhibitor concanavalin A did not. Dynosore quenched the fluorescence of GTTR and could not be tested. Pharmacologic blockade of MET channels with curare or quinine, but not concanavalin A or dynosore, prevented hair cell loss when challenged with gentamicin for up to 96 hours. Taken together, data indicate that the patency of MET channels mediated AG entry into hair cells and its toxicity. Results suggest that limiting permeation of AGs through MET channel or preventing their entry into endolymph are potential therapeutic targets for preventing hair cell death and hearing loss. |
url |
http://europepmc.org/articles/PMC3144223?pdf=render |
work_keys_str_mv |
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