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d-Tubocurarine and berbamine: alkaloids that are permeant blockers of the hair cell's mechano-electrical transducer channel and protect from aminoglycoside toxicity

Kirkwood, Nerissa K., O'Reilly, Molly, Derudas, Marco, Kenyon, Emma J., Huckvale, Rosemary, van Netten, Sietse M., Ward, Simon, Richardson, Guy P. and Kros, Corné J. 2017. 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 11 , 262. 10.3389/fncel.2017.00262

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Uncontrolled Keywords: hair cell, mechanotransduction, hearing loss, ototoxicity, aminoglycosides, d-tubocurarine, berbamine
Publisher: Frontiers Media
ISSN: 1662-5102
Date of First Compliant Deposit: 22 February 2018
Date of Acceptance: 14 August 2017
Last Modified: 31 May 2018 13:38

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