Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652
Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652
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DOI：
10.1038/sj.bjp.0705335
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发表时间：
2003-07-01
影响因子：
7.3
通讯作者：
Witchel, HJ
中科院分区：
文献类型：
--
作者：
Milnes, JT;Crociani, O;Witchel, HJ
1药物阻断人乙醚-a-go-go相关基因（HERG）钾通道通常与获得性长QT综合征和相关的心律失常原有关。本研究的目的是(1)确定和描述选择性5 -羟色胺再摄取抑制剂氟伏沙明对HERG的任何抑制作用，(2)然后确定氟伏沙明是否与迄今为止测试的那些药物的HERG阻断一致的分子决定因素采用全细胞膜片钳技术，在37°c温度下测量了表达HERG通道的哺乳动物细胞系（人胚胎肾293）的异源HERG钾电流（I-HERG）。从+20 mV到-40 mV复极后，I-HERG尾部被氟伏沙明阻断，IC50为3.8 mm。野生型HERG的阻断非常迅速（在10 ms内），并表现出电压依赖性，氟伏沙明还诱导I-HERG的电压依赖性激活向左移位。阻滞的特征与封闭通道（或极迅速发展的开放通道）阻断的成分一致，并依赖于开放和失活的通道状态。减毒失活突变S631A部分降低了氟伏沙明的阻断作用S6突变、Y652A和F656A以及孔螺旋突变体S631A仅部分减弱氟伏沙明对野生型herg5的阻断作用，其浓度可引起对野生型herg5的深度阻断。迄今为止研究的所有herg2阻断药物均显示，与阻断野生型herg5相比，阻断F656突变体通道的效力降低了100倍以上。因此，氟伏沙明在这方面与以前研究过的药物截然不同。
1 Pharmacological blockade of the Human ether-a-go-go related gene (HERG) potassium channel is commonly linked with acquired long QT syndrome and associated proarrhythmia. The objectives of this study were (i) to identify and characterise any inhibitory action on HERG of the selective-serotonin re-uptake inhibitor fluvoxamine, (ii) to then determine whether fluvoxamine shared the consensus molecular determinants of HERG blockade of those drugs so far tested.2 Heterologous HERG potassium current (I-HERG) was measured at 37degreesC, using the whole-cell patch-clamp technique, from a mammalian cell line (Human embryonic kidney 293) expressing HERG channels. I-HERG tails, following repolarisation from +20 to -40 mV, were blocked by fluvoxamine with an IC50 of 3.8 mm.3 Blockade of wild-type HERG was of extremely rapid onset (within 10 ms) and showed voltage dependence, with fluvoxamine also inducing a leftward shift in voltage-dependent activation of I-HERG. Characteristics of block were consistent with a component of closed channel (or extremely rapidly developing open channel) blockade and dependence on open and inactivated channel states. The attenuated-inactivation mutation S631A partially reduced the blocking effect of fluvoxamine.4 The S6 mutations, Y652A and F656A, and the pore helix mutant S631A only partially attenuated blockade by fluvoxamine at concentrations causing profound blockade of wild-type HERG.5 All HERG-blocking pharmaceuticals studied to date have been shown to block F656 mutant channels with over 100-fold reduced potency compared to their blockade of the wild-type channel. Fluvoxamine is therefore quite distinct in this regard from previously studied agents.