Modulation of inhibitory glycine receptors in cultured embryonic mouse hippocampal neurons by zinc, thiol containing redox agents and carnosine.
Modulation of inhibitory glycine receptors in cultured embryonic mouse hippocampal neurons by zinc, thiol containing redox agents and carnosine.
复制标题
锌、含硫醇的氧化还原剂和肌肽对培养的胚胎小鼠海马神经元中抑制性甘氨酸受体的调节。
DOI：
10.1016/j.neuroscience.2006.01.013
复制
发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Zhang,HX
中科院分区：
文献类型：
--
作者：
Thio,LL;Zhang,HX
锌 (Zn2+) 和内源性氧化还原剂（如谷胱甘肽）对抑制性甘氨酸受体的调节可能会改变哺乳动物大脑的抑制作用。尽管海马中 Zn2+ 含量丰富且具有调节甘氨酸受体的能力，但很少有研究检查 Zn2+ 对海马甘氨酸受体的调节作用。氧化还原剂是否调节海马甘氨酸受体仍然未知。本研究使用全细胞记录检查了培养的胚胎小鼠海马神经元中甘氨酸受体介导的电流的 Zn2+ 和氧化还原调节。低于 10 μM 的 Zn2+ 浓度可将低甘氨酸、β-丙氨酸和牛磺酸浓度引起的电流增强 300-400%。 Zn2+ 浓度高于 300 μM 产生几乎完全的抑制。增强 Zn2+ 浓度使三种激动剂的剂量反应曲线向左移动，并降低了甘氨酸和 β-丙氨酸的希尔系数，但不降低牛磺酸。抑制 Zn2+ 浓度使甘氨酸和 β-丙氨酸的剂量反应曲线向右移动，但降低了最大牛磺酸反应。组氨酸残基可能参与增强作用，因为焦碳酸二乙酯和 pH 5.4 减弱了 Zn2+ 甘氨酸电流的增强。 pH 5.4 减弱了甘氨酸电流的 Zn2+ 阻断，但焦碳酸二乙酯却没有。这些发现表明不同的位点介导 Zn2+ 增强和抑制。氧化还原剂谷胱甘肽、二硫苏糖醇、三(2-羧乙基)膦和5,5'-二硫双(2-硝基苯甲酸)不会通过氧化还原机制改变甘氨酸电流。然而，谷胱甘肽和二硫苏糖醇通过螯合干扰 Zn2+ 对甘氨酸电流的影响。肌肽也有类似的作用。因此，含有Zn 2+ 和硫醇的氧化还原剂螯合Zn 2+ 调节海马甘氨酸受体，Zn 2+ 调节机制是激动剂依赖性的。
Modulation of inhibitory glycine receptors by zinc (Zn2+) and endogenous redox agents such as glutathione may alter inhibition in the mammalian brain. Despite the abundance of Zn2+in the hippocampus and its ability to modulate glycine receptors, few studies have examined Zn2+modulation of hippocampal glycine receptors. Whether redox agents modulate hippocampal glycine receptors also remains unknown. This study examined Zn2+and redox modulation of glycine receptor-mediated currents in cultured embryonic mouse hippocampal neurons using whole-cell recordings. Zn2+concentrations below 10 μM potentiated currents elicited by low glycine, β-alanine, and taurine concentrations by 300–400%. Zn2+concentrations above 300 μM produced nearly complete inhibition. Potentiating Zn2+concentrations shifted the dose-response curves for the three agonists to the left and decreased the Hill coefficient for glycine and β-alanine but not taurine. Inhibiting Zn2+concentrations shifted the dose-response curves for glycine and β-alanine to the right but reduced the maximum taurine response. Histidine residues may participate in potentiation because diethyl pyrocarbonate and pH 5.4 diminished Zn2+enhancement of glycine currents. pH 5.4 diminished Zn2+block of glycine currents, but diethyl pyrocarbonate did not. These findings indicate that separate sites mediate Zn2+potentiation and inhibition. The redox agents glutathione, dithiothreitol, tris(2-carboxyethyl)phosphine, and 5,5′-dithiobis(2-nitrobenzoic acid) did not alter glycine currents by a redox mechanism. However, glutathione and dithiothreitol interfered with the effects of Zn2+on glycine currents by chelating it. Carnosine had similar effects. Thus, Zn2+and thiol containing redox agents that chelate Zn2+modulate hippocampal glycine receptors with the mechanism of Zn2+modulation being agonist dependent.