Disruption of intracellular calcium regulation is integral to aminoglycoside-induced hair cell death.
Disruption of intracellular calcium regulation is integral to aminoglycoside-induced hair cell death.
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DOI：
10.1523/jneurosci.4559-12.2013
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发表时间：
2013-04-24
期刊：
影响因子：
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通讯作者：
Rubel EW
中科院分区：
文献类型：
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作者：
Esterberg R;Hailey DW;Coffin AB;Raible DW;Rubel EW
细胞内 Ca2+ 是培养的神经元和感觉细胞生死决定的关键调节因子。 Ca2+ 在这些过程中的作用在体内不太清楚，因为这些细胞的位置通常阻碍细胞内 Ca2+ 动态的可视化。我们生成了转基因斑马鱼品系，它们在侧线的机械感觉毛细胞中表达基因编码的 Ca2+ 指示剂 GCaMP。这些线使我们能够在氨基糖苷类诱导的毛细胞死亡过程中实时监测细胞内 Ca2+ 动态。活幼虫暴露于氨基糖苷类后，垂死的毛细胞会经历细胞内 Ca2+ 的短暂增加，这种情况在线粒体膜电位崩溃后不久就会发生。通过笼式螯合剂或 Ca2+ 效应物的药理学抑制剂抑制细胞内 Ca2+ 升高，可减轻氨基糖苷类暴露的毒性作用。相反，通过笼状 Ca2+ 释放剂人为升高细胞内 Ca2+ 会使毛细胞对氨基糖苷类的毒性作用敏感。这些数据表明，细胞内 Ca2+ 稳态的改变在氨基糖苷类诱导的毛细胞死亡中发挥着重要作用，并表明了阻止耳毒性的几个潜在治疗靶点。
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. Following 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.