Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity

Abdelrahman Alharazneh, Lauren Luk, Markus Huth, Ashkan Monfared, Peter Steyger, Alan G. Cheng, Anthony J. Ricci

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere22347
JournalPLoS One
Volume6
Issue number7
DOIs
StatePublished - 2011

Fingerprint

aminoglycosides
Aminoglycosides
hairs
Cells
Cell death
Gentamicins
Curare
Cell Death
Quinine
gentamicin
Audition
cells
Concanavalin A
Endocytosis
cell death
quinine
endocytosis
hearing
concanavalin A
uptake mechanisms

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Alharazneh, A., Luk, L., Huth, M., Monfared, A., Steyger, P., Cheng, A. G., & Ricci, A. J. (2011). Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. PLoS One, 6(7), [e22347]. https://doi.org/10.1371/journal.pone.0022347

Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. / Alharazneh, Abdelrahman; Luk, Lauren; Huth, Markus; Monfared, Ashkan; Steyger, Peter; Cheng, Alan G.; Ricci, Anthony J.

In: PLoS One, Vol. 6, No. 7, e22347, 2011.

Research output: Contribution to journalArticle

Alharazneh, Abdelrahman ; Luk, Lauren ; Huth, Markus ; Monfared, Ashkan ; Steyger, Peter ; Cheng, Alan G. ; Ricci, Anthony J. / Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. In: PLoS One. 2011 ; Vol. 6, No. 7.
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