白藜芦醇对大鼠皮层神经元GABA_A受体介导电流的影响
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摘要
配体门控离子通道在神经系统中介导快速突触传递从而使细胞能对外部环境的变化快速作出反应。γ氨基丁酸A型受体(GABAA Receptors,GABAARs)是成年哺乳动物中枢神经系统(CNS)内主要的抑制性受体,它们属于配体门控离子超家族。GABAA受体的激活引起氯离子内流,胞内膜电位增加而产生超极化,从而抑制神经元兴奋。因此,GABAA受体在调节神经元兴奋中具有重要的作用。
白藜芦醇(3,4’,5-三羟基-二苯乙烯)是存在于植物中的一种多酚类化合物,葡萄和红葡萄酒中含有大量该物质。实验表明在体和离体模型中白藜芦醇都发挥着有效的神经保护作用。同时白藜芦醇具有抗炎、抗癌、抗血小板凝集和雌激素等作用。但另外一些研究则检测了白藜芦醇对离子通道和受体的药理作用。例如,白藜芦醇对血管内皮细胞的Ca2+激活K+通道具有刺激作用且加强激活大电导钾通道。它也可以抑制心室肌细胞L-型钙电流,减少背根神经节细胞TTX敏感和TTX耐药的Na+电流,抑制淋巴细胞和海马神经元电压激活的钾电流,抑制急性大鼠海马脑片中AMPA/NMDA受体介导的神经元兴奋性突触后电流。然而,目前并没有白藜芦醇对氯离子通道影响的报道,尤其是对中枢神经系统中GABAARs的报道。在本研究中,我们采用全细胞膜片钳记录方法,检测了白藜芦醇对大鼠皮层培养细胞GABAA受体的作用。
在本研究中,我们发现白藜芦醇以浓度依赖的方式可逆地抑制GABAA受体介导的电流,半效抑制浓度为48.7±2.4μM。白藜芦醇减小了GABA诱导电流的最大值并明显改变了EC50值和希尔系数。因此,白藜芦醇是以非竞争性的方式拮抗了大鼠皮层神经元上GABAA受体。白藜芦醇抑制GABAA受体的过程非常迅速,并且这种抑制效果在药物洗脱4分钟之内能完全恢复。这些特点说明白藜芦醇是直接作用于GABAA受体。动力学的分析显示白藜芦醇加速了GABAA受体的脱敏,而加速受体的脱敏是非竞争方式的一个机制。在本实验中,白藜芦醇抑制GABAA受体介导电流,在GABA和白藜芦醇被同时洗脱时没有出现尾电流,而尾电流的出现是开放式通道口阻断(open channel block)理论的一个直接的证据。同时,在不同的模式下,白藜芦醇对GABAA受体介导电流的抑制效果不同,在预给药模式下白藜芦醇的抑制效果更强。在顺序给药模式下,白藜芦醇仍然能对GABAA受体介导电流产生有效的抑制作用,这显示,白藜芦醇可以在通道没有开放的情况下就和受体结合并最终抑制GABAA受体介导的电流,提示我们白藜芦醇的这个结合位点不可能在通道中间,这些结果更加支持了非通道口阻断作用机制推测。基于上述事实,我们推测Resveratrol可能通过变构调节作用抑制GABAA受体。白藜芦醇不会和GABA竞争其在GABAA受体的结合位点,而可能是和GABAA受体上的另一个位点结合并通过变构调节降低GABAA受体对GABA的亲和力。
综上所述,我们的研究结果提示了白藜芦醇能以非竞争性的方式拮抗了皮层神经元上的GABAA受体。白藜芦醇及代谢物可以通过血脑屏障,所以白藜芦醇有可能直接作用于大脑皮层GABAA受体,从而来调节皮层神经系统兴奋性和抑制性以及两者之间的平衡,这为我们研究白藜芦醇受体药理学积累了相关资料。
Ligand-gated ion channels permit cells to respond rapidly to changes in their external environment. They are particularly well known for mediating fast neurotrasmission in the nervous system.γ-Aminobutyric acid type-A receptors (GABA_AR) are the predominant inhibitory neurotransmitter receptors in the mammalian central nervous system (CNS). They belong to the ligand-gated channels superfamily. Activation of GABA_AR leads to an influx of Cl- and increases intracellular membrane potential and generates hyperpolarization,which inhibit neuronal firing. Therefore, the modulation of GABA_AR function would be expected to alter neuronal excitability.
Resveratrol(trans-3,4',5-trihydroxy-stilbene), a natural polyphenols compounds, is present in grapes and wine, which was found to exert potent neuroprotective effects in different in vivo and in vitro models. It has been reported to have a variety of estrogenic, anti-inflammatory, anti-platelet, and anti-carcinogenic effects . But some another research examine the pharmacology function of resveratrol on the ion channel and receptor. For example, resveratrol increased the activity of large-conductance calcium-activated potassium channels in vascular endothelial cells . And resveratrol strengthen to activate the big electric conductivity of potassium channels. It can also inhibit the L-type calcium current of ventricles muscle cell, reduce the TTX sensitive and TTX drug-fast of Na~+ current on the dorsal root ganglion cell, repress the voltage activate of potassium channels current on lymphoid cell and the hippocampal neurons, restain the EPSC of AMPA/NMDAR-mediated current in the acute rat hippocampal brain slice. However, at present, there is no report on the effect of resveratrol on the chlorine ion channels, particularly in GABAARs in CNS (central nervous system). Thus, in the present study, we decided to examine the modulatory effects of resveratrol on native GABAARs in cultured cortex by using the whole-cell patch–clamp recording technique.
In this study, we found that Resveratrol reversibly and concentration-dependently depressed GABA induced current (IGABA), with IC_(50) of 48.7±2.4μM. Resveratrol depressed maximum IGABA, and significant changed the EC_(50) for GABA and Hill coefficient, suggesting that Resveratrol inhibited IGABA through a non-competitive mechanism.The time course of Resveratrol inhibition of GABA_AR was very rapid, and the response was completely reversed after washout for about 4 min. These effects are compatible with the fact that Resveratrol acts directly on GABA_ARs. Kinetic analysis indicated that Resveratrol accelerated the rates of desesnsitization. Enhancement of desensitization is one common mechanism underlying non-competitive inhibition. It is unlikely that Resveratrol acts as an open channel blocker because no rebound current was observed in all experiments after washout of GABA and Resveratrol.The rebound current is the direct evidence of an open channel blocker theory. Besides,the inhibition of Resveratrol on IGABA depended on different drug application mode, and the pre-perfusion of Resveratrol produced the maximal suppressive effect. When applied alone before the application of GABA, Resveratrol also inhibited IGABA, indicating that Resveratrol could bind to the recepter before the channel openning, eliminating the possibility that the acting site of Resveratrol is without the channel center,which further support the idea that the inhibition effect of Resveratrol is not an open channel blocker mechanism. Based on these results, we propose that Resveratrol might exert its action as an allosteric inhibitor. Therefore, Resveratrol is not likely to compete with GABA for its recognition site, but act somewhere else on GABA_ARs that could reduce the GABA’s affinity of GABAARs through changing ion channel conformation.
Taken together, our data clearly demonstrate that Resveratrol significantly inhibit the GABA_A receptor response on cultured cortical neuron through non-competitive mechanism. Resveratrol and its metabolin are able to pass blood brain barrier.So resveratrol could directly combine on GABA_ARs. Thus,resveratrol can modulate excitability ,inhibition and the blance between them of cortex nervous system. Our findings may be helpful to pile up the related receptor pharmacology data of resveratrol.
白藜芦醇(3,4’,5-三羟基-二苯乙烯)是存在于植物中的一种多酚类化合物,葡萄和红葡萄酒中含有大量该物质。实验表明在体和离体模型中白藜芦醇都发挥着有效的神经保护作用。同时白藜芦醇具有抗炎、抗癌、抗血小板凝集和雌激素等作用。但另外一些研究则检测了白藜芦醇对离子通道和受体的药理作用。例如,白藜芦醇对血管内皮细胞的Ca2+激活K+通道具有刺激作用且加强激活大电导钾通道。它也可以抑制心室肌细胞L-型钙电流,减少背根神经节细胞TTX敏感和TTX耐药的Na+电流,抑制淋巴细胞和海马神经元电压激活的钾电流,抑制急性大鼠海马脑片中AMPA/NMDA受体介导的神经元兴奋性突触后电流。然而,目前并没有白藜芦醇对氯离子通道影响的报道,尤其是对中枢神经系统中GABAARs的报道。在本研究中,我们采用全细胞膜片钳记录方法,检测了白藜芦醇对大鼠皮层培养细胞GABAA受体的作用。
在本研究中,我们发现白藜芦醇以浓度依赖的方式可逆地抑制GABAA受体介导的电流,半效抑制浓度为48.7±2.4μM。白藜芦醇减小了GABA诱导电流的最大值并明显改变了EC50值和希尔系数。因此,白藜芦醇是以非竞争性的方式拮抗了大鼠皮层神经元上GABAA受体。白藜芦醇抑制GABAA受体的过程非常迅速,并且这种抑制效果在药物洗脱4分钟之内能完全恢复。这些特点说明白藜芦醇是直接作用于GABAA受体。动力学的分析显示白藜芦醇加速了GABAA受体的脱敏,而加速受体的脱敏是非竞争方式的一个机制。在本实验中,白藜芦醇抑制GABAA受体介导电流,在GABA和白藜芦醇被同时洗脱时没有出现尾电流,而尾电流的出现是开放式通道口阻断(open channel block)理论的一个直接的证据。同时,在不同的模式下,白藜芦醇对GABAA受体介导电流的抑制效果不同,在预给药模式下白藜芦醇的抑制效果更强。在顺序给药模式下,白藜芦醇仍然能对GABAA受体介导电流产生有效的抑制作用,这显示,白藜芦醇可以在通道没有开放的情况下就和受体结合并最终抑制GABAA受体介导的电流,提示我们白藜芦醇的这个结合位点不可能在通道中间,这些结果更加支持了非通道口阻断作用机制推测。基于上述事实,我们推测Resveratrol可能通过变构调节作用抑制GABAA受体。白藜芦醇不会和GABA竞争其在GABAA受体的结合位点,而可能是和GABAA受体上的另一个位点结合并通过变构调节降低GABAA受体对GABA的亲和力。
综上所述,我们的研究结果提示了白藜芦醇能以非竞争性的方式拮抗了皮层神经元上的GABAA受体。白藜芦醇及代谢物可以通过血脑屏障,所以白藜芦醇有可能直接作用于大脑皮层GABAA受体,从而来调节皮层神经系统兴奋性和抑制性以及两者之间的平衡,这为我们研究白藜芦醇受体药理学积累了相关资料。
Ligand-gated ion channels permit cells to respond rapidly to changes in their external environment. They are particularly well known for mediating fast neurotrasmission in the nervous system.γ-Aminobutyric acid type-A receptors (GABA_AR) are the predominant inhibitory neurotransmitter receptors in the mammalian central nervous system (CNS). They belong to the ligand-gated channels superfamily. Activation of GABA_AR leads to an influx of Cl- and increases intracellular membrane potential and generates hyperpolarization,which inhibit neuronal firing. Therefore, the modulation of GABA_AR function would be expected to alter neuronal excitability.
Resveratrol(trans-3,4',5-trihydroxy-stilbene), a natural polyphenols compounds, is present in grapes and wine, which was found to exert potent neuroprotective effects in different in vivo and in vitro models. It has been reported to have a variety of estrogenic, anti-inflammatory, anti-platelet, and anti-carcinogenic effects . But some another research examine the pharmacology function of resveratrol on the ion channel and receptor. For example, resveratrol increased the activity of large-conductance calcium-activated potassium channels in vascular endothelial cells . And resveratrol strengthen to activate the big electric conductivity of potassium channels. It can also inhibit the L-type calcium current of ventricles muscle cell, reduce the TTX sensitive and TTX drug-fast of Na~+ current on the dorsal root ganglion cell, repress the voltage activate of potassium channels current on lymphoid cell and the hippocampal neurons, restain the EPSC of AMPA/NMDAR-mediated current in the acute rat hippocampal brain slice. However, at present, there is no report on the effect of resveratrol on the chlorine ion channels, particularly in GABAARs in CNS (central nervous system). Thus, in the present study, we decided to examine the modulatory effects of resveratrol on native GABAARs in cultured cortex by using the whole-cell patch–clamp recording technique.
In this study, we found that Resveratrol reversibly and concentration-dependently depressed GABA induced current (IGABA), with IC_(50) of 48.7±2.4μM. Resveratrol depressed maximum IGABA, and significant changed the EC_(50) for GABA and Hill coefficient, suggesting that Resveratrol inhibited IGABA through a non-competitive mechanism.The time course of Resveratrol inhibition of GABA_AR was very rapid, and the response was completely reversed after washout for about 4 min. These effects are compatible with the fact that Resveratrol acts directly on GABA_ARs. Kinetic analysis indicated that Resveratrol accelerated the rates of desesnsitization. Enhancement of desensitization is one common mechanism underlying non-competitive inhibition. It is unlikely that Resveratrol acts as an open channel blocker because no rebound current was observed in all experiments after washout of GABA and Resveratrol.The rebound current is the direct evidence of an open channel blocker theory. Besides,the inhibition of Resveratrol on IGABA depended on different drug application mode, and the pre-perfusion of Resveratrol produced the maximal suppressive effect. When applied alone before the application of GABA, Resveratrol also inhibited IGABA, indicating that Resveratrol could bind to the recepter before the channel openning, eliminating the possibility that the acting site of Resveratrol is without the channel center,which further support the idea that the inhibition effect of Resveratrol is not an open channel blocker mechanism. Based on these results, we propose that Resveratrol might exert its action as an allosteric inhibitor. Therefore, Resveratrol is not likely to compete with GABA for its recognition site, but act somewhere else on GABA_ARs that could reduce the GABA’s affinity of GABAARs through changing ion channel conformation.
Taken together, our data clearly demonstrate that Resveratrol significantly inhibit the GABA_A receptor response on cultured cortical neuron through non-competitive mechanism. Resveratrol and its metabolin are able to pass blood brain barrier.So resveratrol could directly combine on GABA_ARs. Thus,resveratrol can modulate excitability ,inhibition and the blance between them of cortex nervous system. Our findings may be helpful to pile up the related receptor pharmacology data of resveratrol.
引文
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