Cloned human inward rectifier K+ channel as a target for class III methanesulfonanilides.
Cloned human inward rectifier K+ channel as a target for class III methanesulfonanilides.
复制标题
克隆的人类内向整流 K 通道作为 III 类甲磺酰苯胺的靶标。
DOI：
10.1161/01.res.77.6.1151
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发表时间：
1995
影响因子：
20.1
通讯作者：
Brown,AM
中科院分区：
文献类型：
--
作者：
Kiehn,J;Wible,B;Ficker,E;Taglialatela,M;Brown,AM
甲磺酰苯胺衍生物如多非利特是广泛使用的第三类心脏抗心律失常药物的成员。甲磺酰苯胺敏感的心脏电流已被确定为 IKr，它是复极外向心脏 K+ 电流 IK 的快速激活成分。 IKr 可能由人类以太相关基因 (hERG) 编码，该基因属于电压依赖性 K+(Kv) 通道家族，具有六个假定的跨膜片段。 hERG 还表达内向整流、甲磺酰苯胺敏感的 K+ 电流。在这里，我们证明 hIRK 是我们从人心脏克隆的内向 K+ 整流器的两跨膜片段家族的成员，它是多非利特的靶点。 hIRK 电流在爪蟾细胞中异源表达，可被亚微摩尔浓度的多非利特阻断（IC50=533 nmol/L，40 mV 和 20°C）。该药对人心脏Kv通道hKv1.2、hKv1.4、hKv1.5或hKv2.1无明显阻断作用。该块与电压、用途相关，并以与开放通道块一致的方式缩短开放时间。虽然稳态阻滞在去极化电位下最强，但即使在超极化电位下，阻滞的恢复也非常慢（-80 mV 时 tau=1.17 秒）。因此，hIRK 的阻断可能在舒张期持续存在，从而可能影响心脏的兴奋性。
Methanesulfonanilide derivatives such as dofetilide are members of the widely used Class III group of cardiac antiarrhythmic drugs. A methanesulfonanilide-sensitive cardiac current has been identified as IKr, the rapidly activating component of the repolarizing outward cardiac K+current, IK. IKrmay be encoded by the human ether-related gene (hERG), which belongs to the family of voltage-dependent K+(Kv) channels having six putative transmembrane segments. The hERG also expresses an inwardly rectifying, methanesulfonanilide-sensitive K+current. Here we show that hIRK, a member of the two-transmembrane-segment family of inward K+rectifiers that we have cloned from human heart, is a target for dofetilide. hIRK currents, expressed heterologously inXenopusoocytes, are blocked by dofetilide at submicromolar concentrations (IC50=533 nmol/L at 40 mV and 20°C). The drug has no significant blocking effect on the human cardiac Kvchannels hKv1.2, hKv1.4, hKv1.5, or hKv2.1. The block is voltage dependent, use dependent, and shortens open times in a manner consistent with open-channel block. While steady state block is strongest at depolarized potentials, recovery from block is very slow even at hyperpolarized potentials (tau=1.17 seconds at −80 mV). Thus, block of hIRK may persist during diastole and might thereby affect cardiac excitability.