Publication

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

Marcotti, W., van Netten, SM. & Kros, CJ., 1-Sep-2005, In : Journal of physiology-London. 567, 2, p. 505-521 17 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Marcotti, W., van Netten, SM., & Kros, CJ. (2005). The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels. Journal of physiology-London, 567(2), 505-521. https://doi.org/10.1113/jphysiol.2005.085951

Author

Marcotti, W ; van Netten, SM ; Kros, CJ. / The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels. In: Journal of physiology-London. 2005 ; Vol. 567, No. 2. pp. 505-521.

Harvard

Marcotti, W, van Netten, SM & Kros, CJ 2005, 'The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels', Journal of physiology-London, vol. 567, no. 2, pp. 505-521. https://doi.org/10.1113/jphysiol.2005.085951

Standard

The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels. / Marcotti, W; van Netten, SM; Kros, CJ.

In: Journal of physiology-London, Vol. 567, No. 2, 01.09.2005, p. 505-521.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Marcotti W, van Netten SM, Kros CJ. The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels. Journal of physiology-London. 2005 Sep 1;567(2):505-521. https://doi.org/10.1113/jphysiol.2005.085951


BibTeX

@article{93d9889da15f4608999d52a7abc4d07a,
title = "The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels",
abstract = "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 mu m, we predict that some 9000 dihydrostreptomycin molecules per second enter each hair cell at therapeutic drug concentrations.",
keywords = "SINGLE CALCIUM CHANNELS, GUINEA-PIG COCHLEA, MECHANOTRANSDUCER CHANNEL, OTOTOXIC ANTIBIOTICS, BULLFROGS SACCULUS, FAST ADAPTATION, RAT-BRAIN, INNER-EAR, BLOCK, GENTAMICIN",
author = "W Marcotti and {van Netten}, SM and CJ Kros",
year = "2005",
month = "9",
day = "1",
doi = "10.1113/jphysiol.2005.085951",
language = "English",
volume = "567",
pages = "505--521",
journal = "Journal of Physiology",
issn = "0022-3751",
publisher = "BLACKWELL PUBLISHING",
number = "2",

}

RIS

TY - JOUR

T1 - The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels

AU - Marcotti, W

AU - van Netten, SM

AU - Kros, CJ

PY - 2005/9/1

Y1 - 2005/9/1

N2 - 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 mu m, we predict that some 9000 dihydrostreptomycin molecules per second enter each hair cell at therapeutic drug concentrations.

AB - 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 mu m, we predict that some 9000 dihydrostreptomycin molecules per second enter each hair cell at therapeutic drug concentrations.

KW - SINGLE CALCIUM CHANNELS

KW - GUINEA-PIG COCHLEA

KW - MECHANOTRANSDUCER CHANNEL

KW - OTOTOXIC ANTIBIOTICS

KW - BULLFROGS SACCULUS

KW - FAST ADAPTATION

KW - RAT-BRAIN

KW - INNER-EAR

KW - BLOCK

KW - GENTAMICIN

U2 - 10.1113/jphysiol.2005.085951

DO - 10.1113/jphysiol.2005.085951

M3 - Article

VL - 567

SP - 505

EP - 521

JO - Journal of Physiology

JF - Journal of Physiology

SN - 0022-3751

IS - 2

ER -

ID: 4364644