ArticleThe Journal of physiology2005
The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels.
Article in The Journal of physiology, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 229 papers.
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229 citing papers in PubMed, 331 citations in OpenAlex.
- Antibiotic-Induced Genotoxicity: Molecular Mechanisms, Cytogenetic Damage, and Implications for Human Health.International journal of molecular sciences · 2026Review
- Transcriptomic profiling of inner ear hair cell spontaneous regeneration reveals the key role of dlx5a.Nature communications · 2026Article
- TNF-α impairs the stria vascularis by inducing pericyte apoptosis via the NF-κB pathway in gentamicin-induced hearing loss.Journal of neuroinflammation · 2026Article
- Cross-species validation of a human age-related hearing loss candidate KLHDC7B as essential for mammalian hearing.Communications biology · 2025Article
- Cohesin protein Smc3 influences kinocilial structure and function.Biology open · 2025Article
- Identification of druggable binding sites and small molecules as modulators of TMC1.Communications biology · 2025Article
- The mechanisms of frequency tuning in gecko auditory hair cells.Hearing research · 2025Review
- Inhibition of GABARAP or GABARAPL1 prevents aminoglycoside- induced hearing loss.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Protective effects of MET channels on aminoglycosides- and cisplatin-induced ototoxicity.International journal of medical sciences · 2025Review
- Aminoglycoside induces RIPOR2 translocation and phosphatidylserine externalization via distinct mechanisms.Frontiers in cellular neuroscience · 2025Article
- Article
- Calcium channel inhibitor and extracellular calcium improve aminoglycoside-induced hair cell loss in zebrafish.Archives of toxicology · 2024Article
- Role of Memantine in Limiting Cochleotoxicity in Rats.Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India · 2024Article
- Suppression of the TGF-β signaling exacerbates degeneration of auditory neurons in kanamycin-induced ototoxicity in mice.Scientific reports · 2024Article
- Role of Oxidative Stress in Sensorineural Hearing Loss.International journal of molecular sciences · 2024Review
- The Piezo channel is a mechano-sensitive complex component in the mammalian inner ear hair cell.Nature communications · 2024Article
- Otoprotection against aminoglycoside- and cisplatin-induced ototoxicity focusing on the upstream drug uptake pathway.Journal of the Chinese Medical Association : JCMA · 2024Review
- Macrophage Depletion Protects Against Cisplatin-Induced Ototoxicity and Nephrotoxicity.bioRxiv : the preprint server for biology · 2023Article
- Mechanisms and Impact of Aminoglycoside-Induced Vestibular Deficits.American journal of audiology · 2023Review
- Aminoglycosides-Related Ototoxicity: Mechanisms, Risk Factors, and Prevention in Pediatric Patients.Pharmaceuticals (Basel, Switzerland) · 2023Review
169 more citing papers are in PubMed but not listed here.
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3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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 microM, we predict that some 9000 dihydrostreptomycin molecules per second enter each hair cell at therapeutic drug concentrations.
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