H(2)O(2)-mediated modulation of cytosolic signaling and organelle function in rat hippocampus.
H(2)O(2)-mediated modulation of cytosolic signaling and organelle function in rat hippocampus.
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DOI：
10.1007/s00424-009-0672-0
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发表时间：
2009-09
影响因子：
4.5
通讯作者：
Mueller, Michael
中科院分区：
文献类型：
--
作者：
Gerich, Florian J.;Funke, Frank;Hildebrandt, Belinda;Fasshauer, Martin;Mueller, Michael
关键词：
从功能异常的线粒体释放的活性氧（ROS）通过调节胞质氧化还原状态和氧化还原敏感蛋白而促进正常和病理生理细胞信号传导。为了确定参与这种信号传导的假定氧化还原靶点，我们将海马神经元暴露于过氧化氢（H2O2）。氧化还原敏感的染料表明，外部应用过氧化氢可能会氧化细胞培养物和急性组织切片中的细胞内目标。在培养的神经元中，H2O2（EC50 118 µ M）诱导细胞内Ca2+升高，这仍然可以在Ca2+撤出和线粒体解偶联后诱发。然而，它是拮抗毒胡萝卜素，丹曲林，2-氨基乙氧基二苯基硼酸酯，和高水平的ryanodine，这表明内质网（ER）作为细胞内的Ca2+存储参与。细胞内积累的内源性产生的H2O2-引起抑制谷胱甘肽过氧化物酶-也释放Ca2+从ER，作为细胞外产生的超氧化物。磷脂酶C（PLC）介导的代谢信号在H2O2的存在下被抑制，但胞浆环腺苷-5 ′-单磷酸（cAMP）水平不受影响。H2O2（0.2 - 5 mM）中度去极化线粒体，停止其在Ca2+和cAMP非依赖性方式的细胞内运输，并直接氧化细胞的烟酰胺腺嘌呤二核苷酸（NADH）和黄素腺嘌呤二核苷酸（FADH 2）。在某种程度上，线粒体去极化反映了先前从ER释放的Ca2+的摄取。我们得出结论，H2O2释放钙离子从内质网通过兰尼碱和肌醇三磷酸受体。线粒体功能没有显着受损，甚至由毫摩尔浓度的H2O2。ROS对Ca2+信号传导和细胞器相互作用的这种调节影响PLC介导的代谢信号传导的功效，并可能有助于调节神经元功能以适应氧化还原条件和代谢供应。本文的在线版本（doi：10.1007/s00424 - 009 - 0672 - 0）包含补充材料，可供授权用户使用。
Reactive oxygen species (ROS) released from (dys-)functioning mitochondria contribute to normal and pathophysiological cellular signaling by modulating cytosolic redox state and redox-sensitive proteins. To identify putative redox targets involved in such signaling, we exposed hippocampal neurons to hydrogen peroxide (H2O2). Redox-sensitive dyes indicated that externally applied H2O2 may oxidize intracellular targets in cell cultures and acute tissue slices. In cultured neurons, H2O2 (EC50 118 µM) induced an intracellular Ca2+ rise which could still be evoked upon Ca2+ withdrawal and mitochondrial uncoupling. It was, however, antagonized by thapsigargin, dantrolene, 2-aminoethoxydiphenyl borate, and high levels of ryanodine, which identifies the endoplasmic reticulum (ER) as the intracellular Ca2+ store involved. Intracellular accumulation of endogenously generated H2O2—provoked by inhibiting glutathione peroxidase—also released Ca2+ from the ER, as did extracellular generation of superoxide. Phospholipase C (PLC)-mediated metabotropic signaling was depressed in the presence of H2O2, but cytosolic cyclic adenosine-5′-monophosphate (cAMP) levels were not affected. H2O2 (0.2–5 mM) moderately depolarized mitochondria, halted their intracellular trafficking in a Ca2+- and cAMP-independent manner, and directly oxidized cellular nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2). In part, the mitochondrial depolarization reflects uptake of Ca2+ previously released from the ER. We conclude that H2O2 releases Ca2+ from the ER via both ryanodine and inositol trisphosphate receptors. Mitochondrial function is not markedly impaired even by millimolar concentrations of H2O2. Such modulation of Ca2+ signaling and organelle interaction by ROS affects the efficacy of PLC-mediated metabotropic signaling and may contribute to the adjustment of neuronal function to redox conditions and metabolic supply. The online version of this article (doi:10.1007/s00424-009-0672-0) contains supplementary material, which is available to authorized users.
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影响因子：
4.8
作者：
Aracena-Parks, Paula;Goonasekera, Sanjeewa A.;Hamilton, Susan L.
通讯作者：
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影响因子：
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通讯作者：
Mueller, Michael