Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death.
Sound perception requires functional hair cell mechanotransduction (MET) machinery, including the MET channels and tip-link proteins. Prior work showed that uptake of ototoxic aminoglycosides (AG) into hair cells requires functional MET channels. In this study, we examined whether tip-link proteins,...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3554584?pdf=render |
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| author | Andrew A Vu Garani S Nadaraja Markus E Huth Lauren Luk John Kim Renjie Chai Anthony J Ricci Alan G Cheng |
| author_facet | Andrew A Vu Garani S Nadaraja Markus E Huth Lauren Luk John Kim Renjie Chai Anthony J Ricci Alan G Cheng |
| author_sort | Andrew A Vu |
| collection | DOAJ |
| description | Sound perception requires functional hair cell mechanotransduction (MET) machinery, including the MET channels and tip-link proteins. Prior work showed that uptake of ototoxic aminoglycosides (AG) into hair cells requires functional MET channels. In this study, we examined whether tip-link proteins, including Cadherin 23 (Cdh23), regulate AG entry into hair cells. Using time-lapse microscopy on cochlear explants, we found rapid uptake of gentamicin-conjugated Texas Red (GTTR) into hair cells from three-day-old Cdh23(+/+) and Cdh23(v2J/+) mice, but failed to detect GTTR uptake in Cdh23(v2J/v2J) hair cells. Pre-treatment of wildtype cochleae with the calcium chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA) to disrupt tip-links also effectively reduced GTTR uptake into hair cells. Both Cdh23(v2J/v2J) and BAPTA-treated hair cells were protected from degeneration caused by gentamicin. Six hours after BAPTA treatment, GTTR uptake remained reduced in comparison to controls; by 24 hours, drug uptake was comparable between untreated and BAPTA-treated hair cells, which again became susceptible to cell death induced by gentamicin. Together, these results provide genetic and pharmacologic evidence that tip-links are required for AG uptake and toxicity in hair cells. Because tip-links can spontaneously regenerate, their temporary breakage offers a limited time window when hair cells are protected from AG toxicity. |
| first_indexed | 2024-12-19T07:12:49Z |
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| id | doaj.art-a733370cccc747ed92743a8e52e93f2e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T07:12:49Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-a733370cccc747ed92743a8e52e93f2e2022-12-21T20:31:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0181e5479410.1371/journal.pone.0054794Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death.Andrew A VuGarani S NadarajaMarkus E HuthLauren LukJohn KimRenjie ChaiAnthony J RicciAlan G ChengSound perception requires functional hair cell mechanotransduction (MET) machinery, including the MET channels and tip-link proteins. Prior work showed that uptake of ototoxic aminoglycosides (AG) into hair cells requires functional MET channels. In this study, we examined whether tip-link proteins, including Cadherin 23 (Cdh23), regulate AG entry into hair cells. Using time-lapse microscopy on cochlear explants, we found rapid uptake of gentamicin-conjugated Texas Red (GTTR) into hair cells from three-day-old Cdh23(+/+) and Cdh23(v2J/+) mice, but failed to detect GTTR uptake in Cdh23(v2J/v2J) hair cells. Pre-treatment of wildtype cochleae with the calcium chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA) to disrupt tip-links also effectively reduced GTTR uptake into hair cells. Both Cdh23(v2J/v2J) and BAPTA-treated hair cells were protected from degeneration caused by gentamicin. Six hours after BAPTA treatment, GTTR uptake remained reduced in comparison to controls; by 24 hours, drug uptake was comparable between untreated and BAPTA-treated hair cells, which again became susceptible to cell death induced by gentamicin. Together, these results provide genetic and pharmacologic evidence that tip-links are required for AG uptake and toxicity in hair cells. Because tip-links can spontaneously regenerate, their temporary breakage offers a limited time window when hair cells are protected from AG toxicity.http://europepmc.org/articles/PMC3554584?pdf=render |
| spellingShingle | Andrew A Vu Garani S Nadaraja Markus E Huth Lauren Luk John Kim Renjie Chai Anthony J Ricci Alan G Cheng Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. PLoS ONE |
| title | Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. |
| title_full | Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. |
| title_fullStr | Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. |
| title_full_unstemmed | Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. |
| title_short | Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. |
| title_sort | integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death |
| url | http://europepmc.org/articles/PMC3554584?pdf=render |
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