Disruption of intracellular calcium regulation is integral to aminoglycoside-induced hair cell death

Abstract

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. ©2013 the authors.