Effect of Daurisoline on hERG Channel Electrophysiological Function and Protein Expression
Effect of Daurisoline on hERG Channel Electrophysiological Function and Protein Expression
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Daurisoline 对 hERG 通道电生理功能和蛋白表达的影响
DOI：
10.1021/np300232b
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发表时间：
2012-09-01
影响因子：
5.1
通讯作者：
Yang, Xiaoyan
中科院分区：
文献类型：
--
作者：
Liu, Qiangni;Mao, Xiaofang;Yang, Xiaoyan
蝙蝠葛苏林碱（1）是从蝙蝠葛（Menispermum dauricum）根茎中分离得到的双苄基异喹啉生物碱。1的抗心律失常作用已在不同的实验动物中得到证实。在先前的研究中，蝙蝠葛苏林（1）以正常的使用依赖性方式延长动作电位时程（APD）。然而，1-诱导APD延长的电生理机制尚未被记录。在本研究中，研究了1对稳定表达hERG通道的人胚肾293（HEK 293）细胞中hERG电流以及mRNA和蛋白质表达的直接影响。结果表明，1以浓度和电压依赖性方式抑制hERG电流。在10 μ M 1的存在下，V-1/2的稳态失活负移15.9 mV，和1加速失活的发病。hERG通道的阻断依赖于通道开放。1和10 μ M时hERG的表达和功能无变化，而30 μ M时hERG表达和hERG电流显著降低。这些结果表明，1，在低于30 μ M的浓度下，对hERG发挥阻断作用，但不影响hERG通道的表达和功能。这可以解释长期使用后长QT综合征的风险相对较低。
Daurisoline (1) is a bis-benzylisoquinoline alkaloid isolated from the rhizomes of Menispermum dauricum. The antiarrhythrnic effect of 1 has been demonstrated in different experimental animals. In previous studies, daurisoline (1) prolonged action potential duration (APD) in a normal use-dependent manner. However, the electrophysiological mechanisms for 1-induced prolongation of APD have not been documented. In the present study, the direct effect of 1 was investigated on the hERG current and the expression of mRNA and protein in human embryonic kidney 293 (HEK293) cells stably expressing the hERG channel. It was shown that 1 inhibits hERG current in a concentration- and voltage-dependent manner. In the presence of 10 mu M 1, steady-state inactivation of V-1/2 was shifted negatively by 15.9 mV, and 1 accelerated the onset of inactivation. Blockade of hERG channels was dependent on channel opening. The expression and function of hERG were unchanged by 1 at 1 and 10 mu M, while hERG expression and the hERG current were decreased significantly by 1 at 30 mu M. These results indicate that 1, at concentrations below 30 mu M, exerts a blocking effect on hERG, but does not affect the expression and function of the hERG channel. This may explain the relatively lower risk of long QT syndrome after long-term usage.