钙调蛋白抑制剂对钾离子通道的直接阻断作用和离子通道与前脂肪细胞增殖的关系
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摘要
背景和目的：N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)是一种众所周知的钙调蛋白(calmodulin)抑制剂,一般被用做研究calmodulin调节细胞内钙信号相关的通路的工具药。本课题旨在利用稳定表达hERG (Kv11.1), hKvl.5和Kir2.1钾通道的HEK293细胞,研究W-7是否对上述电流的直接抑制作用。比较研究了W-7对野生型hERG通道与三种突变型的hERG通道的作用,以明确W-7与hERG通道结合的分子机制。同时也研究了另外一种钙调蛋白抑制剂(W-13)对hERG电流以及hKv1.5和Kir 2.1电流的作用。采用全细胞膜片钳技术记录表达于HEK293细胞的hERG钾电流,hKv1.5和Kir 2.1钾电流。
结果：CaM抑制剂W-7可以抑制hERG钾电流,hKv1.5和Kir 2.1电流。W-7浓度依赖性的抑制hERG电流,半数最大效应浓度IC50为3.5μM。W-7对hERG电流的抑制也具有电压依赖性特点,在+10 mV到+60 mV之间抑制作用更加明显。W-7可使hERG电流电压依赖性稳态激活和失活曲线左移,失活速度加快。电极内液给予10μM W-7对hERG电流产生微弱的抑制作用,弱于细胞外液给予W-7对hERG的抑制作用。在不含EGTA的电极内液中渗透给予500nM CaM(以确保细胞内游离Ca2+维持在生理水平)对hERG电流没有明显的作用,而且不影响细胞外液给予W-7对hERG电流的抑制程度。hERG钾通道S6跨膜结构域的氨基酸突变位点Y652A和F656V,以及孔道区域突变位点S631A可改变W-7对hERG通道的敏感性,W-7对3种突变hERG通道的半数抑制浓度(IC50S)分别为5.5μM,9.8μM和25.4μM。此外W-7也可抑制hKv1.5和Kir2.1电流,其IC50分别为6.5μM和13.4μM。另外一种钙调蛋白抑制剂W-13也可抑制hERG电流,hKv1.5和Kir 2.1电流,IC50分别为19.8μM,75.54μM,43.75μM。
结论：以上研究结果提示钙调蛋白抑制剂W-7可直接阻断表达于HEK293细胞上的hERG钾电流,hKv1.5和Kir 2.1电流。因此在解释W-7对离子通道的影响时需谨慎。
背景和目的：小鼠3T3-L1前脂肪细胞被广泛用作代谢方面的研究,然而,其细胞生理(如功能性离子通道的表达)还未被阐明。本研究主要采用全细胞膜片钳技术,RT-PCR,免疫印迹(western blot),细胞增殖检测方法来探索3T3-L1前脂肪细胞离子通道的表达以及离子通道是否参与细胞增殖调节。
结果：我们发现3T3-L1前脂肪细胞表达三种类型的离子通道,39%的细胞可记录到中电导的钙激活的钾电流(Ca2+-activated K+current(IKca)),15%的细胞记录到内向整流钾电流(Kir),在等渗(1T)条件下只有8%的细胞可记录到氯通道电流,而有趣的是,在低渗透压(0.8T)条件下几乎所有的细胞可记录到氯电流,提示该氯通道为容量激活的氯通道。3T3-L1细胞所记录到的IKir电流可被Ba2+阻断；IKc。电流可以被中等电导的钙激活的钾电流阻断剂clotrimazole阻断,提示所记录到钙激活的钾电流为IKC。电流。Icl可以被氯通道阻断剂DIDS阻断。RT-PCR结果表明了3种通道mRNAs的显著表达,KCa3.1基因(IKca),Kir2.1基因(IKir),和Clcn3(ICl.vol)。我们采用免疫印迹的方法可检测到这三种通道蛋白的表达。MTT和3H胸腺嘧啶渗入法检测细胞增殖结果表明,IKCa阻断剂clotrimazole和ICl.vol阻断剂DIDS均可浓度依赖性的抑制3T3-L1前脂肪细胞的增殖,clotrimazole(3μM)和DIDS (200μM)对细胞增殖的抑制率分别为(10.55±2.97%和60.98±1.79%,P<0.01 vs control)。使用特异性的RNA干扰(short interference)序列,将KCa3.1或Clcn3基因沉默,KCa3.1或Clcn3 siRNA (100nM)均可显著下调IKC。或Icl.vol的mRNA和蛋白表达,并可抑制细胞增殖,最大抑制率分别为(11.29±2.5%和12.76.29±2.7%, P<0.05 vs control)。流式细胞仪分析细胞周期结果表明,clotrimazole和DIDS均可浓度依赖性的增加G0／G1期细胞比例,clotrimazole (3μM)和DIDS (200μM)可使G0／G1期细胞停滞,分别使G0／G1期细胞比例从对照组的50.93±1.64%增加至55.29±3.13%(P<0.01)和70.21±4.09%(P<0.01),并可降低S期的细胞比例。特异性的KCa3.1和Clcn3 siRNA干扰序列将通道基因沉默后可得到与特异性阻断剂相似的结果,与control siRNA组相比,特异性的KCa3.1 siRNA(100nM)使G0／G1期的细胞比例从44.38±4.5%增加至48.56±4.89%(n=3,P<0.01),而Clcn3 siRNA (100nM)可使从G0／G1期的细胞比例从53.64±0.68%(control siRNA)增加到60.54±0.82%(n=3,P<0.05)
结论：这些实验结果首次表明了三种功能性的离子通道包括：中电导的钙激活的钾通道(IKCa),容量敏感的氯通道(Icl.vol)和内向整流钾通道(Kir2.1)共同存在于3T3-L1前脂肪细胞上,其中IKC。和ICl.vol通道可参与调节细胞增殖。
Part I The Calmodulin inhibitors directly blocks potassium channels(hERG, hKvl.5 and Kir 2.1) stably expressed in HEK 293 cells
Background and purpose:N-(6-Aminohexyl)-5-chloro-l-naphthalenesulfonamide (W-7) is a well-known calmodulin inhibitor used as a tool to study calmodulin regulation of intracellular Ca2+ signaling-related process. The present study was to determine whether W-7 would inhibit human ether a-go-go-related gene (hERG or Kv11.1) potassium channel, hKv1.5 channel or hKir2.1 channel expressed in HEK 293 cells. The effect of W-7 on WT hERG channel and three hERG mutants were proformed to identify the molecular determinants of W-7 block of hERG channels.We also investigate the effect of W-13, another camlodulin inhibitor on hERG, hKv1.5 or hKir2.1 potassium channels. The hERG channel current, hKvl.5 channel current or hKir2.1 channel current was recorded with a whole-cell patch-clamp technique.
Results:It was found that the calmodulin inhibitor W-7 blocked hERG, hKv1.5, and hKir2.1 channels. W-7 decreased the hERG current (IhERG) in a concentration-dependent manner (IC50:3.5μM) and voltage-dependent manner, and the inhibition was more significant at depolarization potentials between+10 and+60 mV. The stedy-state activation and inactivation curve of hERG current were negatively shifted and the inactivation of hERG channel was accerlated by W-7. Pipette inclusion of W-7 induced a slow reduction of IhERG.tail, and the inhibitory effect was weaker than bath application of W-7. We included 500 nM calmodulin in an EGTA-free pipette solution (to ensure intracellular free Ca2+ at physiological level) and no significant change in the current was observed in dialysized cells with calmodulin. The hERG mutations in the S6 region Y652A and F656V, and in the pore helix S631A, had the IC50S of 5.5μM,9.8μM, and 25.4μM, respectively. In addition, the compound inhibited hKvl.5 and hKir2.1 channels with IC50S of 6.5 and 13.4μM respectively. W-13 also suppressed these K+ currents; however, the inhibitory effect was remarkably reduced, compared with W-7 with IC50s of 19.8,75.54 and 43.75μM.
Conclusion and implication:These results indicate that the calmodulin inhibitor W-7 exerts a direct channel blocking effect on hERG, hKv1.5 and hKir2.1 channels stably expressed in HEK 293 cells. The caution should be taken in the interpretation of calmodulin regulation of ion channels with W-7.
Part II Ion channels and their role in cell proliferation of 3T3-L1 preadipocytes
Background and Purpose:Mouse 3T3-L1 peradipocytes are widely used for metabolic study; however, cellular physiology (e.g. functional ion channel expression) is not fully understood. The present study was to investigate ion channel expression and functional role of them in regulating cell proliferation using whole cell patch voltage clamp technique, RT-PCR, Western blot, and cell proliferation assay in undifferentiated 3T3-L1 preadipocytes.
Results:We found that three types of ionic currents were present in 3T3-L1 preadi pocytes, including a Ca2+-activated K+ current (IKCa) in 39% cells, an inwardly-rectifying K+ current (IKir) in 15% cells, and a chloride current (ICl) only in 8% cells under isotonic conditions. Interestingly, ICl was observed in all cells with hypotonic (0.8T) insult, suggesting that it is a volume-sensitive ICl (ICl.vol).IKir was inhibited by Ba2+, and IKCa was inhibited by the intermediate conductance IKCa channel blocker clotrimazole. ICl was reduced by the chloride channel blockers DIDS. RT-PCR revealed significant expression of mRNAs:KCa3.1 for IKCa, Kir2.1 for IKir, and Clcn3 for ICl.vol.Proteins of these channels were detected using western blot analysis. Proliferation assay demonstrated that blockade of IKCa with clotrimazole or ICl.vol with DIDS inhibited cell proliferation in a concentration-dependent manner. Knockdown of KCa3.1 or Clcn3 with specific short interference (si)RNAs significantly reduced IKCa or ICl.vol mRNA and channel protein and produced a remarkable suppression of cell proliferation (by 12.76.29±2.7% and 11.29±2.5%, respectively, P<0.05 vs control). Flowcytometry analysis showed that clotrimazole (3μM) and DIDS (200μM) accumulated the cells at G0/G1 phase (from control 50.93±1.64% to 55.29±3.13% for clotrimazole, P<0.01; to 70.21±4.09% for DIDS, P< 0.01). Similar results were obtained with specific siRNAs targeting to KCa3.1 and Clcn3. Specific siRNA increased the cell number of G0/G1 phase(from control siRNA 44.38±4.5% to 48.56±4.89% for KCa3.1 siRNA, P<0.05; from control siRNA 53.64±0.68% to 60.54±0.82% for Clcn3 siRNA, P<0.01).
Conclusions:These results demonstrate the first information that three types of functional ion channel currents, including intermediate-conductance IKCa, ICl.vol, and IKir, are heterogeneously present in 3T3-L1 preadipocytes. IKCa and ICl.vol participate in the regulation of cell proliferation.
结果：CaM抑制剂W-7可以抑制hERG钾电流,hKv1.5和Kir 2.1电流。W-7浓度依赖性的抑制hERG电流,半数最大效应浓度IC50为3.5μM。W-7对hERG电流的抑制也具有电压依赖性特点,在+10 mV到+60 mV之间抑制作用更加明显。W-7可使hERG电流电压依赖性稳态激活和失活曲线左移,失活速度加快。电极内液给予10μM W-7对hERG电流产生微弱的抑制作用,弱于细胞外液给予W-7对hERG的抑制作用。在不含EGTA的电极内液中渗透给予500nM CaM(以确保细胞内游离Ca2+维持在生理水平)对hERG电流没有明显的作用,而且不影响细胞外液给予W-7对hERG电流的抑制程度。hERG钾通道S6跨膜结构域的氨基酸突变位点Y652A和F656V,以及孔道区域突变位点S631A可改变W-7对hERG通道的敏感性,W-7对3种突变hERG通道的半数抑制浓度(IC50S)分别为5.5μM,9.8μM和25.4μM。此外W-7也可抑制hKv1.5和Kir2.1电流,其IC50分别为6.5μM和13.4μM。另外一种钙调蛋白抑制剂W-13也可抑制hERG电流,hKv1.5和Kir 2.1电流,IC50分别为19.8μM,75.54μM,43.75μM。
结论：以上研究结果提示钙调蛋白抑制剂W-7可直接阻断表达于HEK293细胞上的hERG钾电流,hKv1.5和Kir 2.1电流。因此在解释W-7对离子通道的影响时需谨慎。
背景和目的：小鼠3T3-L1前脂肪细胞被广泛用作代谢方面的研究,然而,其细胞生理(如功能性离子通道的表达)还未被阐明。本研究主要采用全细胞膜片钳技术,RT-PCR,免疫印迹(western blot),细胞增殖检测方法来探索3T3-L1前脂肪细胞离子通道的表达以及离子通道是否参与细胞增殖调节。
结果：我们发现3T3-L1前脂肪细胞表达三种类型的离子通道,39%的细胞可记录到中电导的钙激活的钾电流(Ca2+-activated K+current(IKca)),15%的细胞记录到内向整流钾电流(Kir),在等渗(1T)条件下只有8%的细胞可记录到氯通道电流,而有趣的是,在低渗透压(0.8T)条件下几乎所有的细胞可记录到氯电流,提示该氯通道为容量激活的氯通道。3T3-L1细胞所记录到的IKir电流可被Ba2+阻断；IKc。电流可以被中等电导的钙激活的钾电流阻断剂clotrimazole阻断,提示所记录到钙激活的钾电流为IKC。电流。Icl可以被氯通道阻断剂DIDS阻断。RT-PCR结果表明了3种通道mRNAs的显著表达,KCa3.1基因(IKca),Kir2.1基因(IKir),和Clcn3(ICl.vol)。我们采用免疫印迹的方法可检测到这三种通道蛋白的表达。MTT和3H胸腺嘧啶渗入法检测细胞增殖结果表明,IKCa阻断剂clotrimazole和ICl.vol阻断剂DIDS均可浓度依赖性的抑制3T3-L1前脂肪细胞的增殖,clotrimazole(3μM)和DIDS (200μM)对细胞增殖的抑制率分别为(10.55±2.97%和60.98±1.79%,P<0.01 vs control)。使用特异性的RNA干扰(short interference)序列,将KCa3.1或Clcn3基因沉默,KCa3.1或Clcn3 siRNA (100nM)均可显著下调IKC。或Icl.vol的mRNA和蛋白表达,并可抑制细胞增殖,最大抑制率分别为(11.29±2.5%和12.76.29±2.7%, P<0.05 vs control)。流式细胞仪分析细胞周期结果表明,clotrimazole和DIDS均可浓度依赖性的增加G0／G1期细胞比例,clotrimazole (3μM)和DIDS (200μM)可使G0／G1期细胞停滞,分别使G0／G1期细胞比例从对照组的50.93±1.64%增加至55.29±3.13%(P<0.01)和70.21±4.09%(P<0.01),并可降低S期的细胞比例。特异性的KCa3.1和Clcn3 siRNA干扰序列将通道基因沉默后可得到与特异性阻断剂相似的结果,与control siRNA组相比,特异性的KCa3.1 siRNA(100nM)使G0／G1期的细胞比例从44.38±4.5%增加至48.56±4.89%(n=3,P<0.01),而Clcn3 siRNA (100nM)可使从G0／G1期的细胞比例从53.64±0.68%(control siRNA)增加到60.54±0.82%(n=3,P<0.05)
结论：这些实验结果首次表明了三种功能性的离子通道包括：中电导的钙激活的钾通道(IKCa),容量敏感的氯通道(Icl.vol)和内向整流钾通道(Kir2.1)共同存在于3T3-L1前脂肪细胞上,其中IKC。和ICl.vol通道可参与调节细胞增殖。
Part I The Calmodulin inhibitors directly blocks potassium channels(hERG, hKvl.5 and Kir 2.1) stably expressed in HEK 293 cells
Background and purpose:N-(6-Aminohexyl)-5-chloro-l-naphthalenesulfonamide (W-7) is a well-known calmodulin inhibitor used as a tool to study calmodulin regulation of intracellular Ca2+ signaling-related process. The present study was to determine whether W-7 would inhibit human ether a-go-go-related gene (hERG or Kv11.1) potassium channel, hKv1.5 channel or hKir2.1 channel expressed in HEK 293 cells. The effect of W-7 on WT hERG channel and three hERG mutants were proformed to identify the molecular determinants of W-7 block of hERG channels.We also investigate the effect of W-13, another camlodulin inhibitor on hERG, hKv1.5 or hKir2.1 potassium channels. The hERG channel current, hKvl.5 channel current or hKir2.1 channel current was recorded with a whole-cell patch-clamp technique.
Results:It was found that the calmodulin inhibitor W-7 blocked hERG, hKv1.5, and hKir2.1 channels. W-7 decreased the hERG current (IhERG) in a concentration-dependent manner (IC50:3.5μM) and voltage-dependent manner, and the inhibition was more significant at depolarization potentials between+10 and+60 mV. The stedy-state activation and inactivation curve of hERG current were negatively shifted and the inactivation of hERG channel was accerlated by W-7. Pipette inclusion of W-7 induced a slow reduction of IhERG.tail, and the inhibitory effect was weaker than bath application of W-7. We included 500 nM calmodulin in an EGTA-free pipette solution (to ensure intracellular free Ca2+ at physiological level) and no significant change in the current was observed in dialysized cells with calmodulin. The hERG mutations in the S6 region Y652A and F656V, and in the pore helix S631A, had the IC50S of 5.5μM,9.8μM, and 25.4μM, respectively. In addition, the compound inhibited hKvl.5 and hKir2.1 channels with IC50S of 6.5 and 13.4μM respectively. W-13 also suppressed these K+ currents; however, the inhibitory effect was remarkably reduced, compared with W-7 with IC50s of 19.8,75.54 and 43.75μM.
Conclusion and implication:These results indicate that the calmodulin inhibitor W-7 exerts a direct channel blocking effect on hERG, hKv1.5 and hKir2.1 channels stably expressed in HEK 293 cells. The caution should be taken in the interpretation of calmodulin regulation of ion channels with W-7.
Part II Ion channels and their role in cell proliferation of 3T3-L1 preadipocytes
Background and Purpose:Mouse 3T3-L1 peradipocytes are widely used for metabolic study; however, cellular physiology (e.g. functional ion channel expression) is not fully understood. The present study was to investigate ion channel expression and functional role of them in regulating cell proliferation using whole cell patch voltage clamp technique, RT-PCR, Western blot, and cell proliferation assay in undifferentiated 3T3-L1 preadipocytes.
Results:We found that three types of ionic currents were present in 3T3-L1 preadi pocytes, including a Ca2+-activated K+ current (IKCa) in 39% cells, an inwardly-rectifying K+ current (IKir) in 15% cells, and a chloride current (ICl) only in 8% cells under isotonic conditions. Interestingly, ICl was observed in all cells with hypotonic (0.8T) insult, suggesting that it is a volume-sensitive ICl (ICl.vol).IKir was inhibited by Ba2+, and IKCa was inhibited by the intermediate conductance IKCa channel blocker clotrimazole. ICl was reduced by the chloride channel blockers DIDS. RT-PCR revealed significant expression of mRNAs:KCa3.1 for IKCa, Kir2.1 for IKir, and Clcn3 for ICl.vol.Proteins of these channels were detected using western blot analysis. Proliferation assay demonstrated that blockade of IKCa with clotrimazole or ICl.vol with DIDS inhibited cell proliferation in a concentration-dependent manner. Knockdown of KCa3.1 or Clcn3 with specific short interference (si)RNAs significantly reduced IKCa or ICl.vol mRNA and channel protein and produced a remarkable suppression of cell proliferation (by 12.76.29±2.7% and 11.29±2.5%, respectively, P<0.05 vs control). Flowcytometry analysis showed that clotrimazole (3μM) and DIDS (200μM) accumulated the cells at G0/G1 phase (from control 50.93±1.64% to 55.29±3.13% for clotrimazole, P<0.01; to 70.21±4.09% for DIDS, P< 0.01). Similar results were obtained with specific siRNAs targeting to KCa3.1 and Clcn3. Specific siRNA increased the cell number of G0/G1 phase(from control siRNA 44.38±4.5% to 48.56±4.89% for KCa3.1 siRNA, P<0.05; from control siRNA 53.64±0.68% to 60.54±0.82% for Clcn3 siRNA, P<0.01).
Conclusions:These results demonstrate the first information that three types of functional ion channel currents, including intermediate-conductance IKCa, ICl.vol, and IKir, are heterogeneously present in 3T3-L1 preadipocytes. IKCa and ICl.vol participate in the regulation of cell proliferation.
引文
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