Differential oxidative modulation of voltage-dependent K+ currents in rat hippocampal neurons.
Differential oxidative modulation of voltage-dependent K+ currents in rat hippocampal neurons.
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DOI：
10.1152/jn.2002.87.6.2990
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发表时间：
2002-06
影响因子：
2.5
通讯作者：
W. Müller;K. Bittner
中科院分区：
文献类型：
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作者：
W. Müller;K. Bittner
氧化应激通过磷脂酶和线粒体的[Ca 2 +] i依赖性刺激而增强，并且与免疫防御、缺血和兴奋性毒性有关。使用海马神经元的全细胞记录，我们发现花生四烯酸（AA）和过氧化氢（H2 O2）都分别使瞬时K+电流I（A）降低-54和-68%，并分别使稳态失活移动-10和-15 mV。虽然AA在1 μ M的细胞外浓度和1 pM的细胞内浓度下是有效的，但细胞外H2 O2仅在>800 μ M的浓度（0.0027%）下同样有效。与AA相比，H_2O_2使I（A）的激活斜率减小，失活斜率增大，使持续延迟整流电流I（K（V））降低22%，使其激活位移-9mV。细胞内应用的抗氧化剂谷胱甘肽（GSH，2-5 mM）阻断AA的所有影响和还原I（A）的H2 O2。与此相反，细胞内GSH增强还原I（K（V））的H2 O2。通过细胞内应用GSH，过氧化氢对I（A）的激活斜率的降低和失活斜率的增加分别被阻断和逆转为降低。细胞内GSH不能阻止H_2O_2使I（A）的失活和激活以及I（K（V））的激活向更负的电位移动。我们的结论是，AA和H2 O2调节电压激活的钾电流的差异，通过氧化GSH可访问的细胞内和GSH不可访问的细胞外K+通道结构域，从而可能影响神经元的信息处理和氧化损伤。
Oxidative stress is enhanced by [Ca2+]i-dependent stimulation of phospholipases and mitochondria and has been implicated in immune defense, ischemia, and excitotoxicity. Using whole cell recording from hippocampal neurons, we show that arachidonic acid (AA) and hydrogen peroxide (H2O2) both reduce the transient K+ current I(A) by -54 and -68%, respectively, and shift steady-state inactivation by -10 and -15 mV, respectively. While AA was effective at an extracellular concentration of 1 microM and an intracellular concentration of 1 pM, extracellular H2O2 was equally effective only at a concentration >800 microM (0.0027%). In contrast to AA, H2O2 decreased the slope of activation and increased the slope of inactivation of I(A) and reduced the sustained delayed rectifier current I(K(V)) by 22% and shifted its activation by -9 mV. Intracellular application of the antioxidant glutathione (GSH, 2-5 mM) blocked all effects of AA and the reduction of I(A) by H2O2. In contrast, intracellular GSH enhanced reduction of I(K(V)) by H2O2. Decrease of the slope of activation and increase of the slope of inactivation of I(A) by hydrogen peroxide was blocked and reversed to a decrease, respectively, by intracellular application of GSH. Intracellular GSH did not prevent H2O2 to shift inactivation and activation of I(A) and activation of I(K(V)) to more negative potentials. We conclude, that AA and H2O2 modulate voltage-activated K currents differentially by oxidation of GSH accessible intracellular and GSH inaccessible extracellular K+-channel domains, thereby presumably affecting neuronal information processing and oxidative damage.