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首页> 外文期刊>International Journal of Cell Biology >Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone
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Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone

机译：美沙酮对SH-SY5Y细胞中钙延迟延迟调控机制的药理学表征

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Previously, we have shown that SH-SY5Y cells exposed to high concentrations of methadone died due to a necrotic-like cell death mechanism related to delayed calcium deregulation (DCD). In this study, we show that, in terms of their Ca2+ responses to 0.5 mM methadone, SH-SY5Y cells can be pooled into four different groups. In a broad pharmacological survey, the relevance of different Ca2+-related mechanisms on methadone-induced DCD was investigated including extracellular calcium, L-type Ca2+ channels, μ-opioid receptor, mitochondrial inner membrane potential, mitochondrial ATP synthesis, mitochondrial Ca2+/2Na+-exchanger, reactive oxygen species, and mitochondrial permeability transition. Only those compounds targeting mitochondria such as oligomycin, FCCP, CGP 37157, and cyclosporine A were able to amend methadone-induced Ca2+ dyshomeostasis suggesting that methadone induces DCD by modulating the ability of mitochondria to handle Ca2+. Consistently, mitochondria became dramatically shorter and rounder in the presence of methadone. Furthermore, analysis of oxygen uptake by isolated rat liver mitochondria suggested that methadone affected mitochondrial Ca2+ uptake in a respiratory substrate-dependent way. We conclude that methadone causes failure of intracellular Ca2+ homeostasis, and this effect is associated with morphological and functional changes of mitochondria. Likely, this mechanism contributes to degenerative side effects associated with methadone treatment.
机译：以前，我们已经表明，暴露于高浓度美沙酮的SH-SY5Y细胞由于与延迟钙调节失调（DCD）相关的坏死样细胞死亡机制而死亡。在这项研究中，我们表明，就其对0.5 mM美沙酮的Ca2 +反应而言，SH-SY5Y细胞可分为四个不同的组。在广泛的药理研究中，研究了不同Ca2 +相关机制与美沙酮诱导的DCD的相关性，包括细胞外钙，L型Ca2 +通道，μ阿片受体，线粒体内膜电位，线粒体ATP合成，线粒体Ca2 + / 2Na +-交换剂，活性氧和线粒体通透性转变。仅那些靶向线粒体的化合物（例如寡霉素，FCCP，CGP 37157和环孢霉素A）能够修正美沙酮诱导的Ca2 +异位稳态，表明美沙酮通过调节线粒体处理Ca2 +的能力来诱导DCD。一致地，在美沙酮的存在下，线粒体显着变短且变圆。此外，分析离体大鼠肝脏线粒体对氧气的吸收表明，美沙酮以呼吸底物依赖性方式影响线粒体Ca2 +的吸收。我们得出的结论是，美沙酮会导致细胞内Ca2 +稳态失败，并且这种作用与线粒体的形态和功能变化有关。这种机制可能会导致与美沙酮治疗相关的退行性副作用。

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