Journal article 183 views 22 downloads
d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity
Frontiers in Cellular Neuroscience, Volume: 11
Swansea University Author: Emma Kenyon
-
PDF | Version of Record
© 2017 Kirkwood, O'Reilly, Derudas, Kenyon, Huckvale, van Netten, Ward, Richardson and Kros. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0).
Download (3.27MB)
DOI (Published version): 10.3389/fncel.2017.00262
Abstract
Aminoglycoside antibiotics are widely used for the treatment of life-threatening bacterial infections, but cause permanent hearing loss in a substantial proportion of treated patients. The sensory hair cells of the inner ear are damaged following entry of these antibiotics via the mechano-electrical...
Published in: | Frontiers in Cellular Neuroscience |
---|---|
ISSN: | 1662-5102 |
Published: |
Frontiers Media SA
2017
|
Online Access: |
Check full text
|
URI: | https://cronfa.swan.ac.uk/Record/cronfa64048 |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
first_indexed |
2023-09-12T11:17:06Z |
---|---|
last_indexed |
2023-09-12T11:17:06Z |
id |
cronfa64048 |
recordtype |
SURis |
fullrecord |
<?xml version="1.0" encoding="utf-8"?><rfc1807 xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xsd="http://www.w3.org/2001/XMLSchema"><bib-version>v2</bib-version><id>64048</id><entry>2023-08-08</entry><title>d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity</title><swanseaauthors><author><sid>8f07d20c6cb93623521101c62c4e4eb3</sid><ORCID>0000-0002-3898-1866</ORCID><firstname>Emma</firstname><surname>Kenyon</surname><name>Emma Kenyon</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2023-08-08</date><deptcode>BMS</deptcode><abstract>Aminoglycoside antibiotics are widely used for the treatment of life-threatening bacterial infections, but cause permanent hearing loss in a substantial proportion of treated patients. The sensory hair cells of the inner ear are damaged following entry of these antibiotics via the mechano-electrical transducer (MET) channels located at the tips of the hair cell's stereocilia. d-Tubocurarine (dTC) is a MET channel blocker that reduces the loading of gentamicin-Texas Red (GTTR) into rat cochlear hair cells and protects them from gentamicin treatment. Berbamine is a structurally related alkaloid that reduces GTTR labeling of zebrafish lateral-line hair cells and protects them from aminoglycoside-induced cell death. Both compounds are thought to reduce aminoglycoside entry into hair cells through the MET channels. Here we show that dTC (≥6.25 μM) or berbamine (≥1.55 μM) protect zebrafish hair cells in vivo from neomycin (6.25 μM, 1 h). Protection of zebrafish hair cells against gentamicin (10 μM, 6 h) was provided by ≥25 μM dTC or ≥12.5 μM berbamine. Hair cells in mouse cochlear cultures are protected from longer-term exposure to gentamicin (5 μM, 48 h) by 20 μM berbamine or 25 μM dTC. Berbamine is, however, highly toxic to mouse cochlear hair cells at higher concentrations (≥30 μM) whilst dTC is not. The absence of toxicity in the zebrafish assays prompts caution in extrapolating results from zebrafish neuromasts to mammalian cochlear hair cells. MET current recordings from mouse outer hair cells (OHCs) show that both compounds are permeant open-channel blockers, rapidly and reversibly blocking the MET channel with half-blocking concentrations of 2.2 μM (dTC) and 2.8 μM (berbamine) in the presence of 1.3 mM Ca2+ at −104 mV. Berbamine, but not dTC, also blocks the hair cell's basolateral K+ current, IK,neo, and modeling studies indicate that berbamine permeates the MET channel more readily than dTC. These studies reveal key properties of MET-channel blockers required for the future design of successful otoprotectants.</abstract><type>Journal Article</type><journal>Frontiers in Cellular Neuroscience</journal><volume>11</volume><journalNumber/><paginationStart/><paginationEnd/><publisher>Frontiers Media SA</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>1662-5102</issnElectronic><keywords>Hair cell, mechanotransduction, hearing loss, ototoxicity, aminoglycosides, d-tubocurarine, berbamine</keywords><publishedDay>5</publishedDay><publishedMonth>9</publishedMonth><publishedYear>2017</publishedYear><publishedDate>2017-09-05</publishedDate><doi>10.3389/fncel.2017.00262</doi><url>http://dx.doi.org/10.3389/fncel.2017.00262</url><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm>External research funder(s) paid the OA fee (includes OA grants disbursed by the Library)</apcterm><funders/><projectreference/><lastEdited>2023-09-12T12:39:23.9680716</lastEdited><Created>2023-08-08T11:27:37.8802868</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Nerissa K.</firstname><surname>Kirkwood</surname><order>1</order></author><author><firstname>Molly</firstname><surname>O'Reilly</surname><order>2</order></author><author><firstname>Marco</firstname><surname>Derudas</surname><order>3</order></author><author><firstname>Emma</firstname><surname>Kenyon</surname><orcid>0000-0002-3898-1866</orcid><order>4</order></author><author><firstname>Rosemary</firstname><surname>Huckvale</surname><order>5</order></author><author><firstname>Sietse M. van</firstname><surname>Netten</surname><order>6</order></author><author><firstname>Simon E.</firstname><surname>Ward</surname><order>7</order></author><author><firstname>Guy P.</firstname><surname>Richardson</surname><order>8</order></author><author><firstname>Corné J.</firstname><surname>Kros</surname><order>9</order></author></authors><documents><document><filename>64048__28506__72717c0a27eb44d2990bcc4eaef2508b.pdf</filename><originalFilename>64048.VOR.pdf</originalFilename><uploaded>2023-09-12T12:15:56.4227555</uploaded><type>Output</type><contentLength>3424066</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2017 Kirkwood, O'Reilly, Derudas, Kenyon, Huckvale, van Netten, Ward, Richardson and Kros. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0).</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>https://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807> |
spelling |
v2 64048 2023-08-08 d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity 8f07d20c6cb93623521101c62c4e4eb3 0000-0002-3898-1866 Emma Kenyon Emma Kenyon true false 2023-08-08 BMS Aminoglycoside antibiotics are widely used for the treatment of life-threatening bacterial infections, but cause permanent hearing loss in a substantial proportion of treated patients. The sensory hair cells of the inner ear are damaged following entry of these antibiotics via the mechano-electrical transducer (MET) channels located at the tips of the hair cell's stereocilia. d-Tubocurarine (dTC) is a MET channel blocker that reduces the loading of gentamicin-Texas Red (GTTR) into rat cochlear hair cells and protects them from gentamicin treatment. Berbamine is a structurally related alkaloid that reduces GTTR labeling of zebrafish lateral-line hair cells and protects them from aminoglycoside-induced cell death. Both compounds are thought to reduce aminoglycoside entry into hair cells through the MET channels. Here we show that dTC (≥6.25 μM) or berbamine (≥1.55 μM) protect zebrafish hair cells in vivo from neomycin (6.25 μM, 1 h). Protection of zebrafish hair cells against gentamicin (10 μM, 6 h) was provided by ≥25 μM dTC or ≥12.5 μM berbamine. Hair cells in mouse cochlear cultures are protected from longer-term exposure to gentamicin (5 μM, 48 h) by 20 μM berbamine or 25 μM dTC. Berbamine is, however, highly toxic to mouse cochlear hair cells at higher concentrations (≥30 μM) whilst dTC is not. The absence of toxicity in the zebrafish assays prompts caution in extrapolating results from zebrafish neuromasts to mammalian cochlear hair cells. MET current recordings from mouse outer hair cells (OHCs) show that both compounds are permeant open-channel blockers, rapidly and reversibly blocking the MET channel with half-blocking concentrations of 2.2 μM (dTC) and 2.8 μM (berbamine) in the presence of 1.3 mM Ca2+ at −104 mV. Berbamine, but not dTC, also blocks the hair cell's basolateral K+ current, IK,neo, and modeling studies indicate that berbamine permeates the MET channel more readily than dTC. These studies reveal key properties of MET-channel blockers required for the future design of successful otoprotectants. Journal Article Frontiers in Cellular Neuroscience 11 Frontiers Media SA 1662-5102 Hair cell, mechanotransduction, hearing loss, ototoxicity, aminoglycosides, d-tubocurarine, berbamine 5 9 2017 2017-09-05 10.3389/fncel.2017.00262 http://dx.doi.org/10.3389/fncel.2017.00262 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) 2023-09-12T12:39:23.9680716 2023-08-08T11:27:37.8802868 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Nerissa K. Kirkwood 1 Molly O'Reilly 2 Marco Derudas 3 Emma Kenyon 0000-0002-3898-1866 4 Rosemary Huckvale 5 Sietse M. van Netten 6 Simon E. Ward 7 Guy P. Richardson 8 Corné J. Kros 9 64048__28506__72717c0a27eb44d2990bcc4eaef2508b.pdf 64048.VOR.pdf 2023-09-12T12:15:56.4227555 Output 3424066 application/pdf Version of Record true © 2017 Kirkwood, O'Reilly, Derudas, Kenyon, Huckvale, van Netten, Ward, Richardson and Kros. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/ |
title |
d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity |
spellingShingle |
d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity Emma Kenyon |
title_short |
d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity |
title_full |
d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity |
title_fullStr |
d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity |
title_full_unstemmed |
d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity |
title_sort |
d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity |
author_id_str_mv |
8f07d20c6cb93623521101c62c4e4eb3 |
author_id_fullname_str_mv |
8f07d20c6cb93623521101c62c4e4eb3_***_Emma Kenyon |
author |
Emma Kenyon |
author2 |
Nerissa K. Kirkwood Molly O'Reilly Marco Derudas Emma Kenyon Rosemary Huckvale Sietse M. van Netten Simon E. Ward Guy P. Richardson Corné J. Kros |
format |
Journal article |
container_title |
Frontiers in Cellular Neuroscience |
container_volume |
11 |
publishDate |
2017 |
institution |
Swansea University |
issn |
1662-5102 |
doi_str_mv |
10.3389/fncel.2017.00262 |
publisher |
Frontiers Media SA |
college_str |
Faculty of Medicine, Health and Life Sciences |
hierarchytype |
|
hierarchy_top_id |
facultyofmedicinehealthandlifesciences |
hierarchy_top_title |
Faculty of Medicine, Health and Life Sciences |
hierarchy_parent_id |
facultyofmedicinehealthandlifesciences |
hierarchy_parent_title |
Faculty of Medicine, Health and Life Sciences |
department_str |
Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science |
url |
http://dx.doi.org/10.3389/fncel.2017.00262 |
document_store_str |
1 |
active_str |
0 |
description |
Aminoglycoside antibiotics are widely used for the treatment of life-threatening bacterial infections, but cause permanent hearing loss in a substantial proportion of treated patients. The sensory hair cells of the inner ear are damaged following entry of these antibiotics via the mechano-electrical transducer (MET) channels located at the tips of the hair cell's stereocilia. d-Tubocurarine (dTC) is a MET channel blocker that reduces the loading of gentamicin-Texas Red (GTTR) into rat cochlear hair cells and protects them from gentamicin treatment. Berbamine is a structurally related alkaloid that reduces GTTR labeling of zebrafish lateral-line hair cells and protects them from aminoglycoside-induced cell death. Both compounds are thought to reduce aminoglycoside entry into hair cells through the MET channels. Here we show that dTC (≥6.25 μM) or berbamine (≥1.55 μM) protect zebrafish hair cells in vivo from neomycin (6.25 μM, 1 h). Protection of zebrafish hair cells against gentamicin (10 μM, 6 h) was provided by ≥25 μM dTC or ≥12.5 μM berbamine. Hair cells in mouse cochlear cultures are protected from longer-term exposure to gentamicin (5 μM, 48 h) by 20 μM berbamine or 25 μM dTC. Berbamine is, however, highly toxic to mouse cochlear hair cells at higher concentrations (≥30 μM) whilst dTC is not. The absence of toxicity in the zebrafish assays prompts caution in extrapolating results from zebrafish neuromasts to mammalian cochlear hair cells. MET current recordings from mouse outer hair cells (OHCs) show that both compounds are permeant open-channel blockers, rapidly and reversibly blocking the MET channel with half-blocking concentrations of 2.2 μM (dTC) and 2.8 μM (berbamine) in the presence of 1.3 mM Ca2+ at −104 mV. Berbamine, but not dTC, also blocks the hair cell's basolateral K+ current, IK,neo, and modeling studies indicate that berbamine permeates the MET channel more readily than dTC. These studies reveal key properties of MET-channel blockers required for the future design of successful otoprotectants. |
published_date |
2017-09-05T12:39:25Z |
_version_ |
1776831709541564416 |
score |
11.016235 |