Disruption of intracellular calcium regulation is integral to aminoglycoside-induced hair cell death
- Authors
- Esterberg, R., Hailey, D.W., Coffin, A.B., Raible, D.W., and Rubel, E.W.
- ID
- ZDB-PUB-130507-1
- Date
- 2013
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 33(17): 7513-7525 (Journal)
- Registered Authors
- Raible, David
- Keywords
- none
- MeSH Terms
-
- Aminoglycosides/toxicity*
- Animals
- Animals, Genetically Modified
- Calcium/physiology*
- Cell Death/drug effects
- Cell Death/physiology
- Cytoplasm/drug effects
- Cytoplasm/physiology
- Female
- Hair Cells, Vestibular/drug effects
- Hair Cells, Vestibular/physiology*
- Intracellular Fluid/drug effects
- Intracellular Fluid/physiology*
- Lateral Line System/drug effects
- Lateral Line System/physiology
- Male
- Mechanoreceptors/drug effects
- Mechanoreceptors/physiology*
- Zebrafish
- PubMed
- 23616556 Full text @ J. Neurosci.
Intracellular Ca2+ is a key regulator of life or death decisions in cultured neurons and sensory cells. The role of Ca2+ in these processes is less clear in vivo, as the location of these cells often impedes visualization of intracellular Ca2+ dynamics. We generated transgenic zebrafish lines that express the genetically encoded Ca2+ indicator GCaMP in mechanosensory hair cells of the lateral line. These lines allow us to monitor intracellular Ca2+ 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 Ca2+ that occurs shortly after mitochondrial membrane potential collapse. Inhibition of intracellular Ca2+ elevation through either caged chelators or pharmacological inhibitors of Ca2+ effectors mitigates toxic effects of aminoglycoside exposure. Conversely, artificial elevation of intracellular Ca2+ by caged Ca2+ release agents sensitizes hair cells to the toxic effects of aminoglycosides. These data suggest that alterations in intracellular Ca2+ homeostasis play an essential role in aminoglycoside-induced hair cell death, and indicate several potential therapeutic targets to stem ototoxicity.