title: Disruption of intracellular calcium regulation is integral to aminoglycoside-induced hair cell death.
abstract: Intracellular Ca(2+) is a key regulator of life or death decisions in cultured neurons and sensory cells. The role of Ca(2+) in these processes is less clear in vivo, as the location of these cells often impedes visualization of intracellular Ca(2+) dynamics. We generated transgenic zebrafish lines that express the genetically encoded Ca(2+) indicator GCaMP in mechanosensory hair cells of the lateral line. These lines allow us to monitor intracellular Ca(2+) dynamics in real time during aminoglycoside-induced hair cell death. After exposure of live larvae to aminoglycosides, dying hair cells undergo a transient increase in intracellular Ca(2+) that occurs shortly after mitochondrial membrane potential collapse. Inhibition of intracellular Ca(2+) elevation through either caged chelators or pharmacological inhibitors of Ca(2+) effectors mitigates toxic effects of aminoglycoside exposure. Conversely, artificial elevation of intracellular Ca(2+) by caged Ca(2+) release agents sensitizes hair cells to the toxic effects of aminoglycosides. These data suggest that alterations in intracellular Ca(2+) homeostasis play an essential role in aminoglycoside-induced hair cell death, and indicate several potential therapeutic targets to stem ototoxicity.
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Esterberg
authors.forename: Dale W
authors.initials: DW
authors.lastname: Hailey
authors.forename: Allison B
authors.initials: AB
authors.lastname: Coffin
authors.forename: David W
authors.initials: DW
authors.lastname: Raible
authors.forename: Edwin W
authors.initials: EW
authors.lastname: Rubel
mesh_terms: D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D002118:Calcium / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003593:Cytoplasm / Q000187:drug effects / Q000502:physiology; D005260:Female; D018069:Hair Cells, Vestibular / Q000187:drug effects / Q000502:physiology*; D007424:Intracellular Fluid / Q000187:drug effects / Q000502:physiology*; D053403:Lateral Line System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000502:physiology*; D015027:Zebrafish
chemical_list: D000617:Aminoglycosides; D002118:Calcium