麻黄碱直接激活控制心节律的心脏I_（Ks）电流机理的研究
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摘要
麻黄是我国特产而闻名世界的一味中药材,早在两千年前就用于发汗、平喘、止咳。生药麻黄为麻黄(Ephedra sinica stapf)及其同属植物的地上茎,其成分主要包括3组立体异构的生物碱:左旋麻黄碱、右旋伪麻黄碱、左旋去甲基麻黄碱、右旋去甲基伪麻黄碱、左旋甲基麻黄碱、右旋甲基伪麻黄碱。生物碱中以麻黄碱为主,占生物碱总量的80%。麻黄及麻黄碱在临床已经使用多年,而且还作为膳食补充剂等非处方药用来治疗肥胖。麻黄及麻黄碱的广泛使用引发了一系列副作用事件,尤其是心血管系统副作用占47%。传统的观念认为:麻黄治疗疾病及引起副作用的机制是由麻黄碱直接或间接激动α或β肾上腺素受体所致。而我们的研究表明:麻黄碱还可以通过直接增强离子通道电流起作用。
首先,我们利用全细胞扫描的方法,发现麻黄碱对PC12细胞上钾通道有显著的激活作用,但是对PC12细胞上钙通道和DRG细胞钠通道没有影响。而作为其立体异构体的伪麻黄碱对钾电流、钠电流和钙电流都没有作用。
其次,我们研究了麻黄碱对KCNQ1通道的影响。KCNQ1通道(又称Kv7.1,KvLQT1)是一类电压门控钾通道,在心脏中主要与辅助亚基KCNE1共表达形成缓慢激活的、延迟整理的钾电流(I_(Ks)),在心脏动作电位复极化Ⅱ期过程中起关键作用。利用常规膜片钳、双电极膜片钳、点突变、显微注射和转染等试验方法,我们发现麻黄碱在体外表达系统——HEK293细胞和非洲爪蟾卵母细胞中,都能激活KCNQ1/KCNE1通道,激活I_(Ks)电流的EC_(50)=50 nM,而且加药后的激活时间常数(τ_(on))和洗脱时间常数(τ_(off))分别为49 s和400 s。尽管麻黄碱对I_(Ks)电流有显著的激活作用,而伪麻黄碱对I_(Ks)电流几乎没有影响。因此,我们推测并进一步发现了麻黄碱与KCNQ1/KCNE1通道的结合位点是S5-S6之间P-loop上的两个芳香族氨基酸,分别是F296和Y299。由于这两个作为位点在KCNQ通道家族中是保守的,而位于脑组织中的M电流是由KCNQ1的同源基因形成的,故麻黄碱可能在人类的学习和记忆等行为中起重要作用。
再次,为了进一步验证麻黄碱对心血管系统的作用,我们检验了麻黄碱对BALS/c小鼠心电图的影响。结果表明:5 mg/kg麻黄碱能够增加心率49%,缩短QTc 39%。另外,秀丽隐杆线虫(C.elegans)中与KCNQ1通道同源的KQT-3主要位于肠道肌肉,因此我们研究了麻黄碱对线虫排泄的作用,表明:麻黄碱对线虫排泄的周期及排泄间隔影响不大,但却提高线虫排泄成功率Exp/pBoc 20%。
另外,麻黄被用来治疗普通感冒、支气管炎、哮喘和关节炎。我们首次从支气管平滑肌入手,研究麻黄碱对支气管平滑肌细胞(bronchial smooth muscle cells,BSMCs)增殖的影响。300μg/mL麻黄碱对BSMCs增殖影响效果不明显,而600μg/mL麻黄碱却显著抑制了BSMCs的增殖,作用24,48小时后,对BSMCs增殖的抑制率分别达到(25.9±0.43)%和(40.7±0.35)%。
Ephedra is a kind of famous and special local product which has been used to perspire, wheeze and cough for two thousand years in China. The dried medicinal herb of Mahuang is the spigeal stem of Ephedra sinica stapf. Ephedra is composed of three pairs of stereo-isomers alkaloid, including L-ephedrine, D-pseudoephedrine, L-norephedrine, D-norpseudoephedrine, L-methylephedrine, D-methylpseudoephedrine. As the major components, ephedrine (Eph) is about 80 percent of the total alkaloid. Ephedra and Eph have been used in clinical for many years and to treat for obesity as the food assistants. The wide application of Ephedra and Eph induces a series of side effects, especially in cardiovascular system. It is well-known that physiological function and side effects induced by Eph may be through a or (3-adrenoceptor directly or indirectly. However, our findings indicated that Eph could directly activate ion channel.
Firstly, Eph could activate markedly the potassium channel in PC12 cells. But, Eph had no influences on the calcium channel in PC12 cells and sodium channel of DRG cells by whole-cell recording. Oppositely, pseudoephedrine (Pse) could not change the current of K~+, Ca~(2+) and Na~+ channel.
Secondly, the effects of Eph on KCNQ1 channel were also investigated in this paper. KCNQ1 (K_V7.1, K_VLQTl), a kind of voltage-gated potassium channel, which coexpressed with the anxiliary subunit KCNE1 in cardia formed slowly activated-rectified-potassium currents (Iks) and has key contribution on the phase II of repolarization of cardiac action potential. In this study, we found Eph could increase the current of I_(Ks) in vitro (both in Xenopus oocytes and HEK293 cells) by means of patch clamp or two electrode voltage clamp. Then, we demonstrated that Eph, but not pseudoephedrine (Pse), could activate cardiac I_(Ks) currents with EC_(50) = 50 nM. The onset and offset time constants of Eph activation of the I_(Ks) current wereτ_(on) = 49 s andτ_(off) = 400 s, respectively. A pair of Eph binding sites was also shown to occur at F296 and Y299 in the S5-S6 P-loop of the KCNQ1 channel by using of site-mutation, microinjection, transfection, and so on. As the binding sites are conserved highly in the KCNQ family and the M currents in the brain are formed by KCNQ2/KCNQ3 heterotetramer which belonged to the KCNQ family, Eph may have more profound significance on learning and memory. The mechanism of activation by Eph may provide a clue for drug design in the future.
Thirdly, to further corroborate our findings, influences of Eph on the electrocardiographic (ECG) of BALB/c have been studied in the paper. The rats injected Eph with the dose of 5 mg/kg showed an increment of about 49 % in the heart rate and a decrement of about 39 % in the QTc interval. Besides, effects of Eph on defecation of C. elegans have been investigated in the paper also because KQT-3, the homologization of KCNQ1 channel, located mainly at intestine of C.elegans. Eph increased the ration of Exp/pBoc 20 %, whereas had no difference on the cycle period and interval period of defecation.
At last, ephdra has been used to treate as common cold, bronchitis, asthma and arthritis. Until now, it is the first time that the influences of Eph on proliferation of bronchial smooth muscle cells (BSMCs) have been investigated in the paper. There was slight difference on the proliferation of BSMCs in the presence of 300μg/mL Eph. On the contrary, with the dose of 600μg/mL for 24 hours and 48 hours, Eph inhibited the proliferation of BSMCs (25.9±0.43) % and (40.7±0.35) %, respectively.
首先,我们利用全细胞扫描的方法,发现麻黄碱对PC12细胞上钾通道有显著的激活作用,但是对PC12细胞上钙通道和DRG细胞钠通道没有影响。而作为其立体异构体的伪麻黄碱对钾电流、钠电流和钙电流都没有作用。
其次,我们研究了麻黄碱对KCNQ1通道的影响。KCNQ1通道(又称Kv7.1,KvLQT1)是一类电压门控钾通道,在心脏中主要与辅助亚基KCNE1共表达形成缓慢激活的、延迟整理的钾电流(I_(Ks)),在心脏动作电位复极化Ⅱ期过程中起关键作用。利用常规膜片钳、双电极膜片钳、点突变、显微注射和转染等试验方法,我们发现麻黄碱在体外表达系统——HEK293细胞和非洲爪蟾卵母细胞中,都能激活KCNQ1/KCNE1通道,激活I_(Ks)电流的EC_(50)=50 nM,而且加药后的激活时间常数(τ_(on))和洗脱时间常数(τ_(off))分别为49 s和400 s。尽管麻黄碱对I_(Ks)电流有显著的激活作用,而伪麻黄碱对I_(Ks)电流几乎没有影响。因此,我们推测并进一步发现了麻黄碱与KCNQ1/KCNE1通道的结合位点是S5-S6之间P-loop上的两个芳香族氨基酸,分别是F296和Y299。由于这两个作为位点在KCNQ通道家族中是保守的,而位于脑组织中的M电流是由KCNQ1的同源基因形成的,故麻黄碱可能在人类的学习和记忆等行为中起重要作用。
再次,为了进一步验证麻黄碱对心血管系统的作用,我们检验了麻黄碱对BALS/c小鼠心电图的影响。结果表明:5 mg/kg麻黄碱能够增加心率49%,缩短QTc 39%。另外,秀丽隐杆线虫(C.elegans)中与KCNQ1通道同源的KQT-3主要位于肠道肌肉,因此我们研究了麻黄碱对线虫排泄的作用,表明:麻黄碱对线虫排泄的周期及排泄间隔影响不大,但却提高线虫排泄成功率Exp/pBoc 20%。
另外,麻黄被用来治疗普通感冒、支气管炎、哮喘和关节炎。我们首次从支气管平滑肌入手,研究麻黄碱对支气管平滑肌细胞(bronchial smooth muscle cells,BSMCs)增殖的影响。300μg/mL麻黄碱对BSMCs增殖影响效果不明显,而600μg/mL麻黄碱却显著抑制了BSMCs的增殖,作用24,48小时后,对BSMCs增殖的抑制率分别达到(25.9±0.43)%和(40.7±0.35)%。
Ephedra is a kind of famous and special local product which has been used to perspire, wheeze and cough for two thousand years in China. The dried medicinal herb of Mahuang is the spigeal stem of Ephedra sinica stapf. Ephedra is composed of three pairs of stereo-isomers alkaloid, including L-ephedrine, D-pseudoephedrine, L-norephedrine, D-norpseudoephedrine, L-methylephedrine, D-methylpseudoephedrine. As the major components, ephedrine (Eph) is about 80 percent of the total alkaloid. Ephedra and Eph have been used in clinical for many years and to treat for obesity as the food assistants. The wide application of Ephedra and Eph induces a series of side effects, especially in cardiovascular system. It is well-known that physiological function and side effects induced by Eph may be through a or (3-adrenoceptor directly or indirectly. However, our findings indicated that Eph could directly activate ion channel.
Firstly, Eph could activate markedly the potassium channel in PC12 cells. But, Eph had no influences on the calcium channel in PC12 cells and sodium channel of DRG cells by whole-cell recording. Oppositely, pseudoephedrine (Pse) could not change the current of K~+, Ca~(2+) and Na~+ channel.
Secondly, the effects of Eph on KCNQ1 channel were also investigated in this paper. KCNQ1 (K_V7.1, K_VLQTl), a kind of voltage-gated potassium channel, which coexpressed with the anxiliary subunit KCNE1 in cardia formed slowly activated-rectified-potassium currents (Iks) and has key contribution on the phase II of repolarization of cardiac action potential. In this study, we found Eph could increase the current of I_(Ks) in vitro (both in Xenopus oocytes and HEK293 cells) by means of patch clamp or two electrode voltage clamp. Then, we demonstrated that Eph, but not pseudoephedrine (Pse), could activate cardiac I_(Ks) currents with EC_(50) = 50 nM. The onset and offset time constants of Eph activation of the I_(Ks) current wereτ_(on) = 49 s andτ_(off) = 400 s, respectively. A pair of Eph binding sites was also shown to occur at F296 and Y299 in the S5-S6 P-loop of the KCNQ1 channel by using of site-mutation, microinjection, transfection, and so on. As the binding sites are conserved highly in the KCNQ family and the M currents in the brain are formed by KCNQ2/KCNQ3 heterotetramer which belonged to the KCNQ family, Eph may have more profound significance on learning and memory. The mechanism of activation by Eph may provide a clue for drug design in the future.
Thirdly, to further corroborate our findings, influences of Eph on the electrocardiographic (ECG) of BALB/c have been studied in the paper. The rats injected Eph with the dose of 5 mg/kg showed an increment of about 49 % in the heart rate and a decrement of about 39 % in the QTc interval. Besides, effects of Eph on defecation of C. elegans have been investigated in the paper also because KQT-3, the homologization of KCNQ1 channel, located mainly at intestine of C.elegans. Eph increased the ration of Exp/pBoc 20 %, whereas had no difference on the cycle period and interval period of defecation.
At last, ephdra has been used to treate as common cold, bronchitis, asthma and arthritis. Until now, it is the first time that the influences of Eph on proliferation of bronchial smooth muscle cells (BSMCs) have been investigated in the paper. There was slight difference on the proliferation of BSMCs in the presence of 300μg/mL Eph. On the contrary, with the dose of 600μg/mL for 24 hours and 48 hours, Eph inhibited the proliferation of BSMCs (25.9±0.43) % and (40.7±0.35) %, respectively.
引文
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