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The aminoglycoside antibiotic dihydrostreptomycin rapidly enters hair cells through the mechano-electrical transducer channels

journal contribution
posted on 2023-06-08, 08:35 authored by Walter Marcotti, Sietse M van Netten, Corne Kros
The most serious side-effect of the widely used aminoglycoside antibiotics is irreversible intracellular damage to the auditory and vestibular hair cells of the inner ear. The mechanism of entry into the hair cells has not been unequivocally resolved. Here we report that extracellular dihydrostreptomycin not only blocks the mechano-electrical transducer channels of mouse outer hair cells at negative membrane potentials, as previously shown, but also enters the cells through these channels, which are located in the cells' mechanosensory hair bundles. The voltage-dependent blocking kinetics indicate an open-channel block mechanism, which can be well described by a two barrier¿one binding site model, quantifying the antibiotic's block of the channel as well as its permeation in terms of the associated rate constants. The results identify the open transducer channels as the main route for aminoglycoside entry. Intracellularly applied dihydrostreptomycin also blocks the transducer channels, but at positive membrane potentials. However, the potency of the block was two orders of magnitude lower than that due to extracellular dihydrostreptomycin. Extracellular Ca2+ increases the free energy of the barrier nearest the extracellular side and of the binding site for dihydrostreptomycin. This reduces both the entry of dihydrostreptomycin into the channel and the channel's affinity for the drug. In vivo, where the extracellular Ca2+ concentration in the endolymph surrounding the hair bundles is < 100 µM, we predict that some 9000 dihydrostreptomycin molecules per second enter each hair cell at therapeutic drug concentrations.

History

Publication status

  • Published

Journal

Journal of Physiology

ISSN

0022-3751

Issue

2

Volume

567

Page range

505-521

Pages

17.0

Department affiliated with

  • Neuroscience Publications

Notes

All experiments were done in the Kros lab by Kros¿s postdoc Marcotti. Kros initiated, coordinated and oversaw the work and is corresponding author.

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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