KCNQ2钾通道的温度调控机制研究
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摘要
目的：电压依赖型钾离子通道KCNQ2(Kv7.2)在调节神经系统兴奋性方面发挥重要作用。KCNQ2/KCNQ3通道的突变已经被证实是良性家族性新生儿惊厥(benign familial neonatal epilepsy, BFNC)的分子发病基础,KCNQ通道的激活可以减少或降低未成熟大脑的神经元兴奋性的发放和传递。多种因素如神经递质、激素及细胞外离子等通过不同的途径调节KCNQ通道产生的M电流,从而对神经元兴奋性的调节、神经递质的释放和突触的传递等产生影响。因此,研究KCNQ2钾离子通道的调节机制,对了解多种疾病的发病机理和发现新的治疗途径均具有重要的意义。温度对于KCNQ2离子通道的作用尚不清楚,本研究的目的是检测温度对KCNQ2通道的影响,并探讨KCNQ2通道特异性的激活剂氟吡汀对反复热性惊厥(repetitive febrile seizure, RFS)大鼠模型的治疗作用。
方法：
1)采用PCR方法扩增目的基因,构建携带有绿色荧光蛋白(green fluorescent protein, GFP)标签的野生型pEGFP-C1-KCNQ2。在融合表达载体构建成功的基础上,在通道上的这两个区域选择了与BFNC相关的位点进行了定点突变。第一个选择的位点S4区段电压敏感区第214位精氨酸突变为色氨酸(R214W, R→W),第二个位点位于p-loop区段第284位酪氨酸突变为半胱氨酸(Y284C, Y→C)。最后利用重叠延伸(overlap extension) PCR的方法构建R214W、Y284C突变型和孔区截短突变型真核表达载体；
2)用构建成功的野生型和突变型KCNQ2的真核表达载体并分别转染小鼠神经瘤细胞(mouse neuroblastoma cells, N2a)和人胚肾293T细胞(human embryonic kindey, HEK293T cell),荧光共聚焦显微镜(confocal)和Western-blotting检测野生及突变型KCNQ2蛋白在不同温度下的表达情况；将内质网定位质粒pDsRed-ER质粒和野生及突变型KCNQ2的真核表达载体共转染后,Confocal观察野生及突变型KCNQ2蛋白在细胞内的分布及定位情况；
3)全细胞膜片钳记录不同温度下HEK293T细胞上的野生及突变型KCNQ2钾通道的电生理特性；
4)对SPF级10日龄雄性SD大鼠采用45℃热水浴方法制备反复热性惊厥模型,并给以氟吡汀或者苯巴比妥治疗,观察各组大鼠热性惊厥的发作情况。大鼠28日龄时再次诱发热性惊厥,观察不同组大鼠再次惊厥发作的易感性变化。大鼠30日龄时通过水迷宫方法观察大鼠学习记忆能力的变化。
结果：
1)经DNA测序分析证实野生及突变型重组载体构建正确。全细胞膜片钳结果提示野生型pEGFP-C1-KCNQ2表达的电流呈外向、电压依赖性、慢激活特征,达最大稳态电流后表现非失活特征；
2)温度从37℃升高到40℃后,荧光显微镜结果显示转染野生KCNQ2及突变型R214W和Y284C的细胞荧光强度明显增强(p<0.001),同时共定位结果分析提示野生及突变型KCNQ2通道蛋白在细胞内滞留,但是孔区截短型通道的表达在温度升高后没有增加；Western-blotting结果表明温度升高后,野生型和突变型KCNQ2通道总蛋白的表达都显著增加(p<0.05),但是膜表面表达没有明显变化；
3)电生理结果表明温度升高可导致KCNQ2通道的激活曲线明显左移,提示高温情况下KCNQ2通道电压依赖性激活的阈值显著性降低；
4)氟吡汀和苯巴比妥这两种药物都能显著地延长热性惊厥的潜伏期、降低惊厥的发作等级,并使再次惊厥的易感性下降。水迷宫实验结果表明氟吡汀组在学习和记忆方面损伤较非药物处理组小。
结论：温度升高增加了KCNQ2通道在细胞内的表达并且降低了KCNQ2通道的激活阈值,孔区可能是KCNQ2通道转运过程中的重要影响因素。同时,氟吡汀可治疗反复热性惊厥的发作,KCNQ通道作为治疗儿童反复热性惊厥的新靶点值得进一步研究。
Objective:KCNQ2(Kv7.2), Voltage-dependent potassium channels, plays a key role in regulating neuronal excitability. Mutations in neuronal KCNQ2/3subunits, the molecular correlates of M current, have previously been linked with benign familial neonatal epilepsy (BFNC). Activation of KCNQ-channels has been shown to decrease or reduce the propagation of neuronal excitation in the immature central nervous system. A variety of factors such as neurotransmitters, hormones and extracellular ion can regulate M current generated by KCNQ channel and thus control neuronal excitability, neurotransmitter release and synaptic transmission. Therefore, the study on regulatory mechanism of KCNQ2potassium channel is important to understand the pathogenesis of many diseases and find new treatment methods. However, the role of temperature on the expression, distribution and the electrophysiological feature of KCNQ2channels have not been clarified. Our study sought to investigate the impact of temperature elevation on neuronal KCNQ2ion channel, and test whether the KCNQ2channel specific activator flupirtine is also effective for repetitive febrile seizures (RFS) in rats.
Methods:
1) The cDNAs encoding human wild-type KCNQ2were subcloned into pEGFP-C1vector by polymerase chain reaction (PCR). R214W (in the voltage-sensing S4domain) and Y284C(located in the pore region), were introduced into the wild-type KCNQ2construct with the Quick-Change Site-Directed Mutagenesis Kit on the pEGFP-C1vector. Truncated p-loop mutants were engineered in human KCNQ2cDNA by sequence overlap extension PCR.
2) The plasmids were transfected into293T cells or N2a cells respectively. The KCNQ2protein expression at different temperature was detected by fluorescence confocal microscopy and Western-blotting. KCNQ2subunits were coexpressed with an endoplasmic reticulum (ER) marker, pDsRed-ER, and then intracellular location of KCNQ2channels was identified by confocal microscopy.
3) Whole-cell patch clamp was performed to record the effect of temperature electrophysiological activity of KCNQ2potassium channel.
4) RFS were induced in Sprague-Dawley (SD) rats at postnatal day10(P10) in a warm water bath for eight consecutive days with or without the pre-administration of flupirtine or phenobarbital. At P28, febrile seizures were induced to test the rats' susceptivity to febrile seizures. On P30, the Morris water maze was used to test hippocampus-dependent spatial memory.
Results:
1) All of the inserted sequences, as well as the mutated sites, were confirmed by DNA sequencing. The results of whole-cell patch clamp indicated that the current of wild type pEGFP-C1-KCNQ2expressed showed a outward, voltage-dependent, slowly activating and then noninactivating when reached the largest stable current.
2) Confocal microscopy indicated that total fluorescence intensity values of wtKCNQ2, R214W and Y284C were enhanced with the temperature increasing from37℃to40℃(p<0.001). Co-localization of the ER marker with wtKCNQ2and KCNQ2mutants indicated that KCNQ2intracellular localization was increased after temperature elevation. Meanwhile, temperature elevation did not increase the fluorescence intensity of cells transfected with a p-loop truncated mutant. Western-blotting results showed that the total expression but not the surface expression of wt and mutant KCNQ2was increased after Temperature Elevation.
3) Results of electrophysiological study indicated that homomeric KCNQ2channels exhibited a significant leftward shift in the half-maximum activation potential (V1/2) at high temperature, suggested that the voltage-dependence activation trended to be increased by elevated temperature.
4) Both flupirtine and phenobarbital significantly increased the latency, decreased the rate of febrile seizures and reduced the risk of further hyperthermic seizures. The flupirtine-treated group showed less impairment in learning and memory compared with non-treatment group.
Conclusions:The effects of temperature on KCNQ2channel are to raise the rates of activation and increase the ER retention. The p-loop region is critical for temperature-dependent modulation of expression and trafficking of KCNQ2channels. Meanwhile, KCNQ channels may merit further study as an attractive pharmacological target for the treatment of RFS in children.
方法：
1)采用PCR方法扩增目的基因,构建携带有绿色荧光蛋白(green fluorescent protein, GFP)标签的野生型pEGFP-C1-KCNQ2。在融合表达载体构建成功的基础上,在通道上的这两个区域选择了与BFNC相关的位点进行了定点突变。第一个选择的位点S4区段电压敏感区第214位精氨酸突变为色氨酸(R214W, R→W),第二个位点位于p-loop区段第284位酪氨酸突变为半胱氨酸(Y284C, Y→C)。最后利用重叠延伸(overlap extension) PCR的方法构建R214W、Y284C突变型和孔区截短突变型真核表达载体；
2)用构建成功的野生型和突变型KCNQ2的真核表达载体并分别转染小鼠神经瘤细胞(mouse neuroblastoma cells, N2a)和人胚肾293T细胞(human embryonic kindey, HEK293T cell),荧光共聚焦显微镜(confocal)和Western-blotting检测野生及突变型KCNQ2蛋白在不同温度下的表达情况；将内质网定位质粒pDsRed-ER质粒和野生及突变型KCNQ2的真核表达载体共转染后,Confocal观察野生及突变型KCNQ2蛋白在细胞内的分布及定位情况；
3)全细胞膜片钳记录不同温度下HEK293T细胞上的野生及突变型KCNQ2钾通道的电生理特性；
4)对SPF级10日龄雄性SD大鼠采用45℃热水浴方法制备反复热性惊厥模型,并给以氟吡汀或者苯巴比妥治疗,观察各组大鼠热性惊厥的发作情况。大鼠28日龄时再次诱发热性惊厥,观察不同组大鼠再次惊厥发作的易感性变化。大鼠30日龄时通过水迷宫方法观察大鼠学习记忆能力的变化。
结果：
1)经DNA测序分析证实野生及突变型重组载体构建正确。全细胞膜片钳结果提示野生型pEGFP-C1-KCNQ2表达的电流呈外向、电压依赖性、慢激活特征,达最大稳态电流后表现非失活特征；
2)温度从37℃升高到40℃后,荧光显微镜结果显示转染野生KCNQ2及突变型R214W和Y284C的细胞荧光强度明显增强(p<0.001),同时共定位结果分析提示野生及突变型KCNQ2通道蛋白在细胞内滞留,但是孔区截短型通道的表达在温度升高后没有增加；Western-blotting结果表明温度升高后,野生型和突变型KCNQ2通道总蛋白的表达都显著增加(p<0.05),但是膜表面表达没有明显变化；
3)电生理结果表明温度升高可导致KCNQ2通道的激活曲线明显左移,提示高温情况下KCNQ2通道电压依赖性激活的阈值显著性降低；
4)氟吡汀和苯巴比妥这两种药物都能显著地延长热性惊厥的潜伏期、降低惊厥的发作等级,并使再次惊厥的易感性下降。水迷宫实验结果表明氟吡汀组在学习和记忆方面损伤较非药物处理组小。
结论：温度升高增加了KCNQ2通道在细胞内的表达并且降低了KCNQ2通道的激活阈值,孔区可能是KCNQ2通道转运过程中的重要影响因素。同时,氟吡汀可治疗反复热性惊厥的发作,KCNQ通道作为治疗儿童反复热性惊厥的新靶点值得进一步研究。
Objective:KCNQ2(Kv7.2), Voltage-dependent potassium channels, plays a key role in regulating neuronal excitability. Mutations in neuronal KCNQ2/3subunits, the molecular correlates of M current, have previously been linked with benign familial neonatal epilepsy (BFNC). Activation of KCNQ-channels has been shown to decrease or reduce the propagation of neuronal excitation in the immature central nervous system. A variety of factors such as neurotransmitters, hormones and extracellular ion can regulate M current generated by KCNQ channel and thus control neuronal excitability, neurotransmitter release and synaptic transmission. Therefore, the study on regulatory mechanism of KCNQ2potassium channel is important to understand the pathogenesis of many diseases and find new treatment methods. However, the role of temperature on the expression, distribution and the electrophysiological feature of KCNQ2channels have not been clarified. Our study sought to investigate the impact of temperature elevation on neuronal KCNQ2ion channel, and test whether the KCNQ2channel specific activator flupirtine is also effective for repetitive febrile seizures (RFS) in rats.
Methods:
1) The cDNAs encoding human wild-type KCNQ2were subcloned into pEGFP-C1vector by polymerase chain reaction (PCR). R214W (in the voltage-sensing S4domain) and Y284C(located in the pore region), were introduced into the wild-type KCNQ2construct with the Quick-Change Site-Directed Mutagenesis Kit on the pEGFP-C1vector. Truncated p-loop mutants were engineered in human KCNQ2cDNA by sequence overlap extension PCR.
2) The plasmids were transfected into293T cells or N2a cells respectively. The KCNQ2protein expression at different temperature was detected by fluorescence confocal microscopy and Western-blotting. KCNQ2subunits were coexpressed with an endoplasmic reticulum (ER) marker, pDsRed-ER, and then intracellular location of KCNQ2channels was identified by confocal microscopy.
3) Whole-cell patch clamp was performed to record the effect of temperature electrophysiological activity of KCNQ2potassium channel.
4) RFS were induced in Sprague-Dawley (SD) rats at postnatal day10(P10) in a warm water bath for eight consecutive days with or without the pre-administration of flupirtine or phenobarbital. At P28, febrile seizures were induced to test the rats' susceptivity to febrile seizures. On P30, the Morris water maze was used to test hippocampus-dependent spatial memory.
Results:
1) All of the inserted sequences, as well as the mutated sites, were confirmed by DNA sequencing. The results of whole-cell patch clamp indicated that the current of wild type pEGFP-C1-KCNQ2expressed showed a outward, voltage-dependent, slowly activating and then noninactivating when reached the largest stable current.
2) Confocal microscopy indicated that total fluorescence intensity values of wtKCNQ2, R214W and Y284C were enhanced with the temperature increasing from37℃to40℃(p<0.001). Co-localization of the ER marker with wtKCNQ2and KCNQ2mutants indicated that KCNQ2intracellular localization was increased after temperature elevation. Meanwhile, temperature elevation did not increase the fluorescence intensity of cells transfected with a p-loop truncated mutant. Western-blotting results showed that the total expression but not the surface expression of wt and mutant KCNQ2was increased after Temperature Elevation.
3) Results of electrophysiological study indicated that homomeric KCNQ2channels exhibited a significant leftward shift in the half-maximum activation potential (V1/2) at high temperature, suggested that the voltage-dependence activation trended to be increased by elevated temperature.
4) Both flupirtine and phenobarbital significantly increased the latency, decreased the rate of febrile seizures and reduced the risk of further hyperthermic seizures. The flupirtine-treated group showed less impairment in learning and memory compared with non-treatment group.
Conclusions:The effects of temperature on KCNQ2channel are to raise the rates of activation and increase the ER retention. The p-loop region is critical for temperature-dependent modulation of expression and trafficking of KCNQ2channels. Meanwhile, KCNQ channels may merit further study as an attractive pharmacological target for the treatment of RFS in children.
引文
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