非甾体类抗炎药调节A型瞬时外向钾电流的作用和机制研究
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摘要
细胞离子通道的结构和功能正常是维持生命过程的基础,其基因变异和功能障碍与许多疾病的发生和发展有关。离子通道的主要类型有钾、钠、钙、氯和非选择性阳离子通道,各型又分若干亚型。其中钾离子通道在所有可兴奋性和非兴奋性细胞的重要信号传导过程中具有重要作用,其家族成员在调节神经递质释放、心率、胰岛素分泌、神经细胞分泌、上皮细胞电传导、骨骼肌收缩、细胞容积等方面发挥重要作用。病变中的钾离子通道的改变导致机体发生或纠正某些病理生理改变。比如老年性痴呆(Alzheimers'disease, AD),大量的研究发现AD患者体内的一些内源性致病物质与钾通道、钙通道功能异常密切相关,可能通过影响钾通道、钙通道的本身结构或调节过程等,参与AD患者早期记忆损失、认知功能下降等症状的出现。已有大量的研究表明：非甾体类抗炎药(NSAIDs)在体内和体外都可以选择性降低AD的产生,NSAIDs可通过作用于COX等对AD具有一定保护作用。为了进一步了解NSAIDs对于钾离子通道的调控机制,我们选择了两种不同的细胞模型,使用全细胞膜片钳记录,细胞转染等方法对其进行研究。研究主要分为以下两个部分,这些结果显示了NSAIDs对于大鼠小脑颗粒细胞和HEK293细胞中电压依赖型瞬时外向钾离子通道具有双向的调控作用。
第一部分：以前的实验观察到NSAIDs在不同的细胞模型上对于细胞膜离子通道具有调节作用。在这部分研究中我们选取两种NSAIDs:甲芬那酸(mefenamic acid, MA)和氟芬那酸(flufenamic acid, FFA),应用全细胞膜电流记录技术,分别研究了FFA、MA对于原代培养的大鼠小脑颗粒细胞电压门控瞬时失活外向钾通道电流(IA)的影响机制。以FFA为例,结果表明：FFA在细胞外浓度为20μM至1 mM之间时,能可逆性地抑制IA,这种抑制效果呈现浓度依赖性。然而,当FFA细胞外浓度降低到10μM以下时,IA反而显著性地增大。更高浓度的FFA对激活和失活的动力学参数也有显著影响,使电流的稳态激活和失活曲线分别向右移动10 mV和9 mV,提示FFA与IA通道亲和力是呈电压依赖性的。细胞内加入FFA能显著性的增加IA电流,但是当细胞外同时加入FFA时,不能改变细胞外FFA对于IA的抑制作用,表明FFA是通过细胞内外两种不同的途径作用的。进一步观察到：细胞内加入FFA增大IA电流的这一效应可被其它环氧化酶抑制剂和花生四烯酸所模拟,提示细胞内加入FFA增大IA电流的作用很可能是通过抑制环氧化酶和提高细胞内花生四烯酸水平。这些实验结果表明了FFA能够在神经元中以不同的浓度双向调节IA电流并且可能涉及到细胞内、外两种不同调节机制。
第二部分：人胚胎肾细胞(HEK293)是研究细胞膜电生理学和离子通道的一种最常用的表达系统。在这部分研究中我们以HEK293为细胞模型,采用瞬时转染pEGFP-N1／Kv4.2和pEGFP-N1／Kv4.3通道质粒到HEK293细胞株,原代培养小脑颗粒细胞和全细胞膜片钳记录等方法,主要观察比较了Kv4.2、Kv4.3通道IA电流电生理学特性及FFA/MA对其调控作用机制。结果表明：小脑颗粒细胞上IA电流和转染的Kv4.2、Kv4.3通道电流均具有明显的A型电流特征。Kv4.3的衰减速率明显小于Kv4.2并且接近于天然颗粒细胞上IA通道电流的衰减速率,而单独表达的Kv4.3通道电流幅度也大于Kv4.2,同样接近于天然颗粒细胞。当细胞外分别给予适当浓度的FFA和MA时,能可逆性地抑制IA,然而在低浓度时, IA反而显著性增大。细胞内分别加入FFA和MA也能显著性的增加IA电流,这一过程也能被细胞内加入花生四烯酸所模拟。进一步分别在细胞内加入FFA和MA,并对其激活失活参数予以比较,观察到无论给药FFA/MA前后,或细胞内外给药, Kv4.2较之颗粒细胞IA通道动力学敏感性提高,而Kv4.3与颗粒细胞上IA通道相比更不易激活和失活。细胞外FFA/MA对Kv4.2通道IA电流的稳态激活参数和稳态失活参数的改变一致,这提示我们FFA和MA在细胞外对于Kv4.2的作用机制相似,这一点也与FFA/MA对小脑颗粒细胞上的相同细胞外作用一致,当细胞内给予一定浓度FFA对Kv4.2通道和颗粒神经元上IA通道电流的稳态激活参数和稳态失活参数的改变一致,这提示我们Kv4.2通道亚单位在FFA/MA对于颗粒神经元的细胞内调控起到了主要作用,主要参与调控颗粒神经元,A通道的电生理门控特性。
Cell structure and normal function of ion channels is to maintain basic life processes. The genetic variation and dysfunction are related to the occurrence and development of many diseases. Potassium channel plays an important role during signal transduction of all excitable and non-excitable cells. Changes of lesions in potassium channels lead to the occurrence or the body to correct some of the pathophysiological changes. Such as senile dementia (Alzheimers'disease, AD), a large number of studies have found pathogenicity of some endogenous substances of AD patients is closely related to dysfunctions of potassium channel and calcium channel, and involved in AD patients with early memory loss, cognitive decline and other symptoms appeared through affecting the structure of potassium channel and calcium channel or processes of modulation. Extensive research has been shown that:non-steroidal anti-inflammatory drugs (NSAIDs) can selectively reduce the production of AD in vitro and in vivo, NSAIDs have some protective effect against AD by acting on COX and so. We chose two different cell models, using the whole cell patch clamp recording, cell transfection and other methods to get further understanding of the mechanisms regulated by NSAIDs on the potassium ion channels. The research is divided into the following two sections, the results show that NSAIDs bi-directionally modulated voltage-dependent transient outward K+ channel on rat cerebellar granule cells and HEK293 cells.
Part One:It is observed that NSAIDs can regulate membrane ion channels in different cell models in previous experiments. In this part of the study, we selected two NSAIDs:Mefenamic acid (MA) and flufenamic acid(FFA). Take FFA for example, results show that at a higher concentration FFA reversibly inhibited IA in a dose-dependent manner. However, FFA at a low concentration significantly increased the current amplitude of IA. A higher concentration of FFA had a significant effect on the kinetic parameters of the steady-state activation and inactivation process, suggesting that the binding affinity of FFA to IA channels may be state-dependent. Intracellular application of FFA could significantly increase the IA amplitude but did not alter the inhibited effect induced by extracellular application of FFA, implying that FFA may exert its effect from both the inside and outside sites of the channel. Furthermore, the activation of current induced by intracellular application of FFA could mimic other cyclooxygenase inhibitors and arachidonic acid. Our data demonstrate how FFA is able to bidirectionally modulate IA channels in neurons at different concentrations and by different methods of application and that two different mechanisms may be involved.
Part Two:The results showed that IA in cultured rat cerebellar granule neurons and Kv4.2, Kv4.3 expressed in HEK293 cells both displayed "A"-type current properties. Appropriate concentration of FFA/MA reversibly inhibited IA but significantly increased the current amplitude of IA at lower concentration. Intracellular application of FFA/MA could significantly increase the IA amplitude and can be mimicked by intracellular arachidonic acid application. Comparitive of its activation parameters, Kv4.2 channel kinetics is more sensitive than that of the granule cells no matter of before and after administration, or intracellular and extracellular administration, while less sensitive to that of Kv4.3. Extracellular FFA/MA on the Kv4.2 channel IA current in steady-state activation parameters and steady-state inactivation parameters consistent with the changes. This suggests that FFA and MA have similar mechanisms on the Kv4.2 channel extracellularly, it is also consistent with the effect of FFA/MA on cerebellar granule cells extracellularly. When exposed to a certain concentration of FFA, steady-state activation parameters and inactivation parameters consistent with the changes on the Kv4.2 channel and granule neurons of the IA channel current. This suggests that Kv4.2 channel subtypes play a major role in the regulation of FFA/MA on the intracellular granule neurons, mainly involved in regulation of granule neurons IA channel electrophysiological gating.
第一部分：以前的实验观察到NSAIDs在不同的细胞模型上对于细胞膜离子通道具有调节作用。在这部分研究中我们选取两种NSAIDs:甲芬那酸(mefenamic acid, MA)和氟芬那酸(flufenamic acid, FFA),应用全细胞膜电流记录技术,分别研究了FFA、MA对于原代培养的大鼠小脑颗粒细胞电压门控瞬时失活外向钾通道电流(IA)的影响机制。以FFA为例,结果表明：FFA在细胞外浓度为20μM至1 mM之间时,能可逆性地抑制IA,这种抑制效果呈现浓度依赖性。然而,当FFA细胞外浓度降低到10μM以下时,IA反而显著性地增大。更高浓度的FFA对激活和失活的动力学参数也有显著影响,使电流的稳态激活和失活曲线分别向右移动10 mV和9 mV,提示FFA与IA通道亲和力是呈电压依赖性的。细胞内加入FFA能显著性的增加IA电流,但是当细胞外同时加入FFA时,不能改变细胞外FFA对于IA的抑制作用,表明FFA是通过细胞内外两种不同的途径作用的。进一步观察到：细胞内加入FFA增大IA电流的这一效应可被其它环氧化酶抑制剂和花生四烯酸所模拟,提示细胞内加入FFA增大IA电流的作用很可能是通过抑制环氧化酶和提高细胞内花生四烯酸水平。这些实验结果表明了FFA能够在神经元中以不同的浓度双向调节IA电流并且可能涉及到细胞内、外两种不同调节机制。
第二部分：人胚胎肾细胞(HEK293)是研究细胞膜电生理学和离子通道的一种最常用的表达系统。在这部分研究中我们以HEK293为细胞模型,采用瞬时转染pEGFP-N1／Kv4.2和pEGFP-N1／Kv4.3通道质粒到HEK293细胞株,原代培养小脑颗粒细胞和全细胞膜片钳记录等方法,主要观察比较了Kv4.2、Kv4.3通道IA电流电生理学特性及FFA/MA对其调控作用机制。结果表明：小脑颗粒细胞上IA电流和转染的Kv4.2、Kv4.3通道电流均具有明显的A型电流特征。Kv4.3的衰减速率明显小于Kv4.2并且接近于天然颗粒细胞上IA通道电流的衰减速率,而单独表达的Kv4.3通道电流幅度也大于Kv4.2,同样接近于天然颗粒细胞。当细胞外分别给予适当浓度的FFA和MA时,能可逆性地抑制IA,然而在低浓度时, IA反而显著性增大。细胞内分别加入FFA和MA也能显著性的增加IA电流,这一过程也能被细胞内加入花生四烯酸所模拟。进一步分别在细胞内加入FFA和MA,并对其激活失活参数予以比较,观察到无论给药FFA/MA前后,或细胞内外给药, Kv4.2较之颗粒细胞IA通道动力学敏感性提高,而Kv4.3与颗粒细胞上IA通道相比更不易激活和失活。细胞外FFA/MA对Kv4.2通道IA电流的稳态激活参数和稳态失活参数的改变一致,这提示我们FFA和MA在细胞外对于Kv4.2的作用机制相似,这一点也与FFA/MA对小脑颗粒细胞上的相同细胞外作用一致,当细胞内给予一定浓度FFA对Kv4.2通道和颗粒神经元上IA通道电流的稳态激活参数和稳态失活参数的改变一致,这提示我们Kv4.2通道亚单位在FFA/MA对于颗粒神经元的细胞内调控起到了主要作用,主要参与调控颗粒神经元,A通道的电生理门控特性。
Cell structure and normal function of ion channels is to maintain basic life processes. The genetic variation and dysfunction are related to the occurrence and development of many diseases. Potassium channel plays an important role during signal transduction of all excitable and non-excitable cells. Changes of lesions in potassium channels lead to the occurrence or the body to correct some of the pathophysiological changes. Such as senile dementia (Alzheimers'disease, AD), a large number of studies have found pathogenicity of some endogenous substances of AD patients is closely related to dysfunctions of potassium channel and calcium channel, and involved in AD patients with early memory loss, cognitive decline and other symptoms appeared through affecting the structure of potassium channel and calcium channel or processes of modulation. Extensive research has been shown that:non-steroidal anti-inflammatory drugs (NSAIDs) can selectively reduce the production of AD in vitro and in vivo, NSAIDs have some protective effect against AD by acting on COX and so. We chose two different cell models, using the whole cell patch clamp recording, cell transfection and other methods to get further understanding of the mechanisms regulated by NSAIDs on the potassium ion channels. The research is divided into the following two sections, the results show that NSAIDs bi-directionally modulated voltage-dependent transient outward K+ channel on rat cerebellar granule cells and HEK293 cells.
Part One:It is observed that NSAIDs can regulate membrane ion channels in different cell models in previous experiments. In this part of the study, we selected two NSAIDs:Mefenamic acid (MA) and flufenamic acid(FFA). Take FFA for example, results show that at a higher concentration FFA reversibly inhibited IA in a dose-dependent manner. However, FFA at a low concentration significantly increased the current amplitude of IA. A higher concentration of FFA had a significant effect on the kinetic parameters of the steady-state activation and inactivation process, suggesting that the binding affinity of FFA to IA channels may be state-dependent. Intracellular application of FFA could significantly increase the IA amplitude but did not alter the inhibited effect induced by extracellular application of FFA, implying that FFA may exert its effect from both the inside and outside sites of the channel. Furthermore, the activation of current induced by intracellular application of FFA could mimic other cyclooxygenase inhibitors and arachidonic acid. Our data demonstrate how FFA is able to bidirectionally modulate IA channels in neurons at different concentrations and by different methods of application and that two different mechanisms may be involved.
Part Two:The results showed that IA in cultured rat cerebellar granule neurons and Kv4.2, Kv4.3 expressed in HEK293 cells both displayed "A"-type current properties. Appropriate concentration of FFA/MA reversibly inhibited IA but significantly increased the current amplitude of IA at lower concentration. Intracellular application of FFA/MA could significantly increase the IA amplitude and can be mimicked by intracellular arachidonic acid application. Comparitive of its activation parameters, Kv4.2 channel kinetics is more sensitive than that of the granule cells no matter of before and after administration, or intracellular and extracellular administration, while less sensitive to that of Kv4.3. Extracellular FFA/MA on the Kv4.2 channel IA current in steady-state activation parameters and steady-state inactivation parameters consistent with the changes. This suggests that FFA and MA have similar mechanisms on the Kv4.2 channel extracellularly, it is also consistent with the effect of FFA/MA on cerebellar granule cells extracellularly. When exposed to a certain concentration of FFA, steady-state activation parameters and inactivation parameters consistent with the changes on the Kv4.2 channel and granule neurons of the IA channel current. This suggests that Kv4.2 channel subtypes play a major role in the regulation of FFA/MA on the intracellular granule neurons, mainly involved in regulation of granule neurons IA channel electrophysiological gating.
引文
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ACKNOWLEDGEMENTS
The study was supported by a grant from the Committee of Science and Technology, Shanghai (04DZ19901), National Basic Research Program of China (2007CB512303) and Shanghai Leading Academic Discipline Project (B111). Guang Yang was supported by the National Talent Training Fund in Basic Research of China (No. J0630643).
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ACKNOWLEDGEMENTS
The study was supported by a grant from the Committee of Science and Technology, Shanghai (04DZ19901), National Basic Research Program of China (2007CB512303) and Shanghai Leading Academic Discipline Project (B111). Guang Yang was supported by the National Talent Training Fund in Basic Research of China (No. J0630643).
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