Inhibition of cardiac HERG potassium channels by antidepressant maprotiline
Inhibition of cardiac HERG potassium channels by antidepressant maprotiline
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DOI：
10.1016/j.ejphar.2005.10.036
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发表时间：
2006-02-15
影响因子：
5
通讯作者：
Sánchez-Chapula, JA
中科院分区：
文献类型：
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作者：
Ferrer-Villada, T;Navarro-Polanco, RA;Sánchez-Chapula, JA
许多药物阻断延迟整流K+通道，延长心脏动作电位持续时间。在这里，我们研究了马普替林对HEK-293细胞和非洲爪蟾卵母细胞中表达的人乙醚-a-go-go相关基因（HERG） K通道电压依赖性阻断的分子机制。0 mV下对HERG表达的HEK-293细胞和卵母细胞的IC50分别为5.2和23.7 μ M。马普罗替林对卵母细胞中HERG表达的阻断作用随着膜的渐进式去极化而增强，并伴随着通道激活的电压依赖性的负移。马普替林的效价通过关键芳香残基F656T的点突变降低了7倍，Y652A的点突变降低了3倍，均位于S6结构域。突变Y652A逆转了马普罗替林对HERG通道阻滞的电压依赖性。总之，这些结果表明HERG的电压依赖性阻断是由药物结合位点的关键成分Y652的可及性的门控依赖性变化引起的。(c) 2005 Elsevier B.V.版权所有
Many drugs block delayed rectifier K+ channels and prolong the cardiac action potential duration. Here we investigate the molecular mechanisms of voltage-dependent block of human ether-a-go-go-related gene (HERG) K channels expressed in cells HEK-293 and Xenopus oocytes by maprotiline. The IC50 determined at 0 mV on HERG expressed HEK-293 cell and oocytes was 5.2 and 23.7 mu M, respectively. Block of HERG expressed in oocytes by maprotiline was enhanced by progressive membrane depolarization and accompanied by a negative shift in the voltage dependence of channel activation. The potency of maprotiline was reduced 7-fold by point mutation of a key aromatic residue (F656T) and 3-fold for Y652A, both located in the S6 domain. The mutation Y652A inverted the voltage dependence of HERG channel block by maprotiline. Together, these results Suggest that voltage-dependent block of HERG results from gating dependent changes in the accessibility of Y652, a critical component of the drug binding site. (c) 2005 Elsevier B.V. All rights reserved.