生物碱类CFTR氯离子通道激活剂的筛选及性质研究
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摘要
囊性纤维化跨膜电导调节因子(cystic fibrosis transmembrane conductance regulator,CFTR)是一种受cAMP调节的氯离子通道。CFTR的表达非常广泛,主要参与电解质及液体的转运。该通道活动的异常与多种疾病的病理发生相关:CFTR氯离子通道功能丧失或活性降低可导致慢性胰腺炎、多囊肾病、男性不育、习惯性便秘和干眼病等;而功能的过度激活则可导致分泌性腹泻、多囊肾病等。CFTR氯离子通道高效、特异性调节剂对于研究CFTR相关疾病的病理机制和治疗具有重要价值。
本文的目的是从生物碱中筛选野生型CFTR氯离子通道的激活剂并对其分子药理学特征进行系统研究。利用碘离子高度敏感的CFTR氯离子通道荧光测定细胞模型,对46种生物碱类化合物进行了筛选,得到了16种能够明显促进碘离子转运的活性化合物。对二氢辣椒素、辣椒素、茶碱、盐酸罂粟碱激活CFTR氯离子通道的分子药理学性质进行了系统研究。发现了(1)辣椒素和二氢辣椒素对CFTR离子通道活性的最大激活效率Vmax分别是0.4 mM/S和0.5 mM/S;它们与CFTR的亲和力分别是152±7.4μ?Μ和40.4±6.8μM;辣椒素和二氢辣椒素均不能激活?F508-CFTR氯离子通道活性,也不能纠正?F508-CFTR细胞质膜定位障碍;辣椒素和二氢辣椒素在CFTR上的结合位点可能与genistein在CFTR上的结合位点存在一定的重叠。辣椒素和二氢辣椒素激活CFTR氯离子通道活性可能是其导泻的生理活性的原因之一。(2)茶碱能够激活CFTR氯离子通道,Vmax值和Kd值分别是130±1.27μ?M和0.57±0.04 mM/S;茶碱对ΔF508-CFTR和G551D-CFTR的离子通道功能障碍均没有纠正活性,也不能纠正ΔF508-CFTR细胞质膜定位障碍;茶碱的上述活性与以往发现的其众多生物学活性之间的关系还不清楚。(3)盐酸罂粟碱对CFTR氯离子通道具有较强的激活作用,Vmax值为0.85 mM/s,Kd值为20μM;盐酸罂粟碱能够激活?F508-CFTR氯离子通道活性,但是对G551D-CFTR氯离子通道活性没有激活作用,其对?F508-CFTR氯离子通道激活作用的Vmax和Kd值分别为0.08 mM/s和40μM;盐酸罂粟碱与genistein在CFTR上的结合位点不存在重叠。盐酸罂粟碱的CFTR氯离子通道激活活性可能是其降压作用的原因之一。
本研究在国际上首次以天然化合物生物碱为对象,筛选CFTR氯离子通道的天然激活剂,并发现了多种活性较强、结构多样的天然化合物。我们的研究为生物碱活性研究补充了新内容。首次对盐酸罂粟碱、二氢辣椒素、茶碱等生物碱类野生型CFTR氯离子通道激活剂进行了系统的分子药理学研究。首次提供证据显示CFTR氯离子通道作为盐酸罂粟碱、二氢辣椒素、茶碱等生物碱类化合物体内活性的分子靶点。
CFTR(cystic fibrosis transmembrane conductance regulator) is a cAMP dependent chloride channel. It is extensively expressed by epithelial cells lined airway, gastrointestinal tract, pancreatic, sweat gland, testis,et al, and plays key roles in transport of electrolyte and fluid. The abnormal activity of CFTR chloride channel is related to pathogenesis of several diseases. Malfunction will result in cystic fibrosis, chronic pancreatitis, male sterility, habitual constipation, keratoconjunctivitis sicca (KCS, also called dry eye syndrome). Over activation of CFTR is related to diarrhea, polycystic kidney disease (ADPKD). High affinity CFTR regulators are important in studying CFTR-related diseases and mechanisms involved.
The purpose of this study is to identify natural alkaloid compounds that can stimulate activation of wild-type human CFTR (wt-CFTR) chloride channel and molecular pharmacological mechanisms related. An FRT cell line stably coexpressing wt-CFTR and the high halide sensitive YFP (YFP-H148Q) cell based assay were used in the study. 14 alkaloids that can stimulate iodide transport mediated by wt-CFTR were identified from 46 natural alkaloids, among which dihydrocapsaicin, capsaicin, theophylline, and papaverine HCl exhibit the highest activities. In this paper molecular pharmacological properties of these compounds were systematically investigated. We found that (1) dihydrocapsaicin, capsaicin can dependently actived wt-CFTR, with affinities of 152±7.4μ?Μand 40.4±6.8, respectively; with maximal potencies of 0.4 mM/S and 0.5 mM/S, respectively. None pf the compounds stimulatedΔF508-CFTR mediated iodide influx or corrected its misprocessing defect. Further investigation manifested that the capsaicinoids might share common binding site in CFTR with genbistein, known CFTR activator. CFTR activation activity might account part of laxative effect of capsaicinoids. (2) Theophylline also activated CFTR choloride channel, with Kd and Vmax values were 130±1.27μ?M and 0.57±0.04 mM/S, respectively. Theophylline had no effect on the most common CFTR mutation forms of CFTR (ΔF508-CFTR and G551D-CFTR), and it could not correct the misprocessing defect ofΔF508-CFTR. The relationship between CFTR activation activity of theophylline and its multiphysiological effect is not clear. (3) Papaverine HCl could stimulate both wt CFTR andΔF508-CFTR chloride channels, but not G551D-CFTR chloride channel, with Vmax values are 0.85 mM/s and 0.08 mM/s, respectively; Kd values are 20μM and 40μM, respectively. Initial studies showed that papaverine HCl did not share common binding site in CFTR with genbistein.
We identified several CFTR activators from natural alkaloid compounds and systematically investigated their pharmacological properties. Our results integrated (in part) and supplemented activities of alkaloid compounds. Molecular pharmacological studies of several alkaloids (dihydrocapsaicin, capsaicin, theophylline, and papaverine HCl) showed that CFTR protein might be one of the molecule drug targets of these compounds.
本文的目的是从生物碱中筛选野生型CFTR氯离子通道的激活剂并对其分子药理学特征进行系统研究。利用碘离子高度敏感的CFTR氯离子通道荧光测定细胞模型,对46种生物碱类化合物进行了筛选,得到了16种能够明显促进碘离子转运的活性化合物。对二氢辣椒素、辣椒素、茶碱、盐酸罂粟碱激活CFTR氯离子通道的分子药理学性质进行了系统研究。发现了(1)辣椒素和二氢辣椒素对CFTR离子通道活性的最大激活效率Vmax分别是0.4 mM/S和0.5 mM/S;它们与CFTR的亲和力分别是152±7.4μ?Μ和40.4±6.8μM;辣椒素和二氢辣椒素均不能激活?F508-CFTR氯离子通道活性,也不能纠正?F508-CFTR细胞质膜定位障碍;辣椒素和二氢辣椒素在CFTR上的结合位点可能与genistein在CFTR上的结合位点存在一定的重叠。辣椒素和二氢辣椒素激活CFTR氯离子通道活性可能是其导泻的生理活性的原因之一。(2)茶碱能够激活CFTR氯离子通道,Vmax值和Kd值分别是130±1.27μ?M和0.57±0.04 mM/S;茶碱对ΔF508-CFTR和G551D-CFTR的离子通道功能障碍均没有纠正活性,也不能纠正ΔF508-CFTR细胞质膜定位障碍;茶碱的上述活性与以往发现的其众多生物学活性之间的关系还不清楚。(3)盐酸罂粟碱对CFTR氯离子通道具有较强的激活作用,Vmax值为0.85 mM/s,Kd值为20μM;盐酸罂粟碱能够激活?F508-CFTR氯离子通道活性,但是对G551D-CFTR氯离子通道活性没有激活作用,其对?F508-CFTR氯离子通道激活作用的Vmax和Kd值分别为0.08 mM/s和40μM;盐酸罂粟碱与genistein在CFTR上的结合位点不存在重叠。盐酸罂粟碱的CFTR氯离子通道激活活性可能是其降压作用的原因之一。
本研究在国际上首次以天然化合物生物碱为对象,筛选CFTR氯离子通道的天然激活剂,并发现了多种活性较强、结构多样的天然化合物。我们的研究为生物碱活性研究补充了新内容。首次对盐酸罂粟碱、二氢辣椒素、茶碱等生物碱类野生型CFTR氯离子通道激活剂进行了系统的分子药理学研究。首次提供证据显示CFTR氯离子通道作为盐酸罂粟碱、二氢辣椒素、茶碱等生物碱类化合物体内活性的分子靶点。
CFTR(cystic fibrosis transmembrane conductance regulator) is a cAMP dependent chloride channel. It is extensively expressed by epithelial cells lined airway, gastrointestinal tract, pancreatic, sweat gland, testis,et al, and plays key roles in transport of electrolyte and fluid. The abnormal activity of CFTR chloride channel is related to pathogenesis of several diseases. Malfunction will result in cystic fibrosis, chronic pancreatitis, male sterility, habitual constipation, keratoconjunctivitis sicca (KCS, also called dry eye syndrome). Over activation of CFTR is related to diarrhea, polycystic kidney disease (ADPKD). High affinity CFTR regulators are important in studying CFTR-related diseases and mechanisms involved.
The purpose of this study is to identify natural alkaloid compounds that can stimulate activation of wild-type human CFTR (wt-CFTR) chloride channel and molecular pharmacological mechanisms related. An FRT cell line stably coexpressing wt-CFTR and the high halide sensitive YFP (YFP-H148Q) cell based assay were used in the study. 14 alkaloids that can stimulate iodide transport mediated by wt-CFTR were identified from 46 natural alkaloids, among which dihydrocapsaicin, capsaicin, theophylline, and papaverine HCl exhibit the highest activities. In this paper molecular pharmacological properties of these compounds were systematically investigated. We found that (1) dihydrocapsaicin, capsaicin can dependently actived wt-CFTR, with affinities of 152±7.4μ?Μand 40.4±6.8, respectively; with maximal potencies of 0.4 mM/S and 0.5 mM/S, respectively. None pf the compounds stimulatedΔF508-CFTR mediated iodide influx or corrected its misprocessing defect. Further investigation manifested that the capsaicinoids might share common binding site in CFTR with genbistein, known CFTR activator. CFTR activation activity might account part of laxative effect of capsaicinoids. (2) Theophylline also activated CFTR choloride channel, with Kd and Vmax values were 130±1.27μ?M and 0.57±0.04 mM/S, respectively. Theophylline had no effect on the most common CFTR mutation forms of CFTR (ΔF508-CFTR and G551D-CFTR), and it could not correct the misprocessing defect ofΔF508-CFTR. The relationship between CFTR activation activity of theophylline and its multiphysiological effect is not clear. (3) Papaverine HCl could stimulate both wt CFTR andΔF508-CFTR chloride channels, but not G551D-CFTR chloride channel, with Vmax values are 0.85 mM/s and 0.08 mM/s, respectively; Kd values are 20μM and 40μM, respectively. Initial studies showed that papaverine HCl did not share common binding site in CFTR with genbistein.
We identified several CFTR activators from natural alkaloid compounds and systematically investigated their pharmacological properties. Our results integrated (in part) and supplemented activities of alkaloid compounds. Molecular pharmacological studies of several alkaloids (dihydrocapsaicin, capsaicin, theophylline, and papaverine HCl) showed that CFTR protein might be one of the molecule drug targets of these compounds.
引文
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