钙库调控钙离子通道特异分子的筛选及其相关特性的研究
摘要
钙库调控钙离子通道(store-operated calcium channel, SOC)是一种在多种细胞中存在的钙离子通道。其基本的门控机制是当胞内钙库逐渐排空时,位于钙库膜上的信号分子STIM1(stromal interaction moleculel)将会聚集并与细胞膜上的SOC通道蛋白Orai1相互结合,改变其构象并打开通道。SOC通道可以调控许多生理功能,比如可以调控一些基因的转录、胞内某些酶的活性以及细胞的胞吐作用等等。同时,SOC通道功能的异常也与一些疾病相关,比如重症联合免疫缺陷综合症等。而目前由于已知的SOC通道的拮抗剂和激动剂数量有限,且基本上都没有特异性,使得人们对SOC通道的深入了解受到了阻碍。
本论文针对这一点利用果蝇S2细胞,应用胞内荧光强度检测的实验方法构建了SOC通道特异分子的筛选模型,并利用该模型对部分从中草药中提取的小分子化合物进行筛选。经反复验证,最终得到了一个有拮抗效果的小分子科罗索酸,并初步研究了科罗索酸对SOC的拮抗机制。
1.SOC通道特异分子筛选模型的构建
选择果蝇S2细胞作为SOC通道特异分子筛选的细胞模型。经摸索,发现25℃、无CO2的培养条件是较适宜S2细胞生长的条件。在该培养条件下,应用SOC通道激动剂TG、胞内钙探针Fluo-4AM以及FlexStation细胞内钙检测的技术,构建了SOC通道特异分子筛选的基本细胞模型,并利用该模型对三种已知的钙通道拮抗剂Gd3+、SKF-96365和2APB进行测试。结果显示,基本模型能够很好地检测出这三种拮抗剂对SOC通道的作用特性及效果,表明基本细胞模型是可靠、稳定的；为后续的药物筛选实验打下了基础。
2.天然提取化合物的筛选及活性化合物的作用机理初探
应用所构建的SOC通道特异分子的筛选模型,对本所从中草药中所分离出的小分子化1选。经验证,最终得到了一个对SOC通道有拮抗效果的小分子化合物科罗索酸。之后,我们对科罗索酸的拮抗机理进行了探索,发现科罗索酸能够拮抗内质网释放钙离子,推测科罗索酸可能通过阻碍内质网的排空进而拮抗SOC通道。
Store-operated calcium channel (SOC) is a kind of calcium channels existing in many cell types. The basic operating mechanism of SOC is that when the intracellular calcium store depletes, the signal molecules, stromal interaction molecule 1 (STIM1), located on the membrane of the store, will aggregate and bind to the channel protein Orai1, then change the channel protein's structure and open the channel. SOC can regulate many physiological processes, such as regulating transcriptions of some genes, controlling the activity of some enzymes and modulating exocytosis. Meanwhile, SOC can be related to some diseases like severe combind immunodeficiency. However, up to present, there are not enough antagonists and agonists of SOC, and also almost all of the known antagonists and agonists are lack of specificity, which impede our profound understanding of SOC.
Our research aims at getting some specific antagonists or agonists of SOC which will make people know SOC better. Using Drosophila S2 cells and the technique of intracellular Ca2+concentration measurement, the basal cellular assay model for screening for the antagonist and agonist of SOC was established. After examing the dependability and stability of the basal cell model, we screened the compounds that were extracted for Chinese herbal medicine. Finally we got an effective compound corosolic acid, which could block store-operated calcium entry (SOCE). The inhibiting effect of corosolic acid was conformed by many experiments. We further explored the inhibiting mechanism of corosolic acid.
1.The establishment of cellular model of screening for antagonist and agonist of SOC
Using Drosophila S2 cells as the cellular model to screen for the antagonist and agonist of SOC. After exploring, the optimized growing environment for Drosophila S2 cells is that 25℃without CO2. Using the known SOC agonist thapsigargin (TG), intracellular calcium indicator Fluo-4 AM, we established the basal cellular assay model for screening antagonist and agonist of SOC. Then using three known Ca2+ channel inhibitors Gd3+、SKF-96365 and 2APB, we examined the dependability and stability of the basal model. And the results show that the basal model is dependable and stable.
2. The screening of compounds extracted from Chinese herbal medicine and the exploring of the property of target compound
Using the established model, we screened some compounds extracted from Chinese herbal medicine and finally got an effective compound corosolic acid which exhibited inhibiting effect. And many other experiments were carried on to confirm corosolic acid can block SOC. Then we explored corosolic acid's inhibiting mechanism and found that corosolic acid could block calcium release from the store. Therefore, we infer that corosolic acid probably take the inhibiting effect through blocking calcium release.
本论文针对这一点利用果蝇S2细胞,应用胞内荧光强度检测的实验方法构建了SOC通道特异分子的筛选模型,并利用该模型对部分从中草药中提取的小分子化合物进行筛选。经反复验证,最终得到了一个有拮抗效果的小分子科罗索酸,并初步研究了科罗索酸对SOC的拮抗机制。
1.SOC通道特异分子筛选模型的构建
选择果蝇S2细胞作为SOC通道特异分子筛选的细胞模型。经摸索,发现25℃、无CO2的培养条件是较适宜S2细胞生长的条件。在该培养条件下,应用SOC通道激动剂TG、胞内钙探针Fluo-4AM以及FlexStation细胞内钙检测的技术,构建了SOC通道特异分子筛选的基本细胞模型,并利用该模型对三种已知的钙通道拮抗剂Gd3+、SKF-96365和2APB进行测试。结果显示,基本模型能够很好地检测出这三种拮抗剂对SOC通道的作用特性及效果,表明基本细胞模型是可靠、稳定的；为后续的药物筛选实验打下了基础。
2.天然提取化合物的筛选及活性化合物的作用机理初探
应用所构建的SOC通道特异分子的筛选模型,对本所从中草药中所分离出的小分子化1选。经验证,最终得到了一个对SOC通道有拮抗效果的小分子化合物科罗索酸。之后,我们对科罗索酸的拮抗机理进行了探索,发现科罗索酸能够拮抗内质网释放钙离子,推测科罗索酸可能通过阻碍内质网的排空进而拮抗SOC通道。
Store-operated calcium channel (SOC) is a kind of calcium channels existing in many cell types. The basic operating mechanism of SOC is that when the intracellular calcium store depletes, the signal molecules, stromal interaction molecule 1 (STIM1), located on the membrane of the store, will aggregate and bind to the channel protein Orai1, then change the channel protein's structure and open the channel. SOC can regulate many physiological processes, such as regulating transcriptions of some genes, controlling the activity of some enzymes and modulating exocytosis. Meanwhile, SOC can be related to some diseases like severe combind immunodeficiency. However, up to present, there are not enough antagonists and agonists of SOC, and also almost all of the known antagonists and agonists are lack of specificity, which impede our profound understanding of SOC.
Our research aims at getting some specific antagonists or agonists of SOC which will make people know SOC better. Using Drosophila S2 cells and the technique of intracellular Ca2+concentration measurement, the basal cellular assay model for screening for the antagonist and agonist of SOC was established. After examing the dependability and stability of the basal cell model, we screened the compounds that were extracted for Chinese herbal medicine. Finally we got an effective compound corosolic acid, which could block store-operated calcium entry (SOCE). The inhibiting effect of corosolic acid was conformed by many experiments. We further explored the inhibiting mechanism of corosolic acid.
1.The establishment of cellular model of screening for antagonist and agonist of SOC
Using Drosophila S2 cells as the cellular model to screen for the antagonist and agonist of SOC. After exploring, the optimized growing environment for Drosophila S2 cells is that 25℃without CO2. Using the known SOC agonist thapsigargin (TG), intracellular calcium indicator Fluo-4 AM, we established the basal cellular assay model for screening antagonist and agonist of SOC. Then using three known Ca2+ channel inhibitors Gd3+、SKF-96365 and 2APB, we examined the dependability and stability of the basal model. And the results show that the basal model is dependable and stable.
2. The screening of compounds extracted from Chinese herbal medicine and the exploring of the property of target compound
Using the established model, we screened some compounds extracted from Chinese herbal medicine and finally got an effective compound corosolic acid which exhibited inhibiting effect. And many other experiments were carried on to confirm corosolic acid can block SOC. Then we explored corosolic acid's inhibiting mechanism and found that corosolic acid could block calcium release from the store. Therefore, we infer that corosolic acid probably take the inhibiting effect through blocking calcium release.
引文
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