Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification
Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification
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DOI：
10.1073/pnas.1004021107
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发表时间：
2010-08-31
影响因子：
11.1
通讯作者：
Delpon, Eva
中科院分区：
文献类型：
--
作者：
Caballero, Ricardo;Dolz-Gaiton, Pablo;Delpon, Eva
心内整流电流（IK1）的升高和降低均与严重心律失常有关。Flecainide是一种广泛使用的抗心律失常药物，具有心室促心律失常作用，同时有效控制与Kir2.1通道编码基因突变相关的室性心律失常，该基因突变可降低IK1 （Andersen综合征）。在这里，我们描述了flecainide诱导的Kir2.1通道（I-Kir2.1）和IK1在心室肌细胞中产生的电流增加的电生理和分子基础。Flecainide通过降低同四聚体Kir2.1通道对细胞内多胺的亲和力，从而减少电流的内向整流，从而增加了由Kir2.1通道产生的向外I-Kir2.1。Flecainide与通道细胞质结构域的HI环相互作用，Cys311对该效应至关重要。这就解释了为什么flecainide不会增加IKir2.2和I-Kir2.3，因为Kir2.2和Kir2.3通道在等效位置没有显示Cys残基。我们进一步发现，用flecainide孵育可增加膜中功能性Kir2.1通道的表达，这一效应也由Cys311确定。事实上，在药理学上，氟氯胺可以拯救Andersen综合征患者中发现的R67W通道突变，而不是R218W通道突变。此外，我们的发现为C端细胞质结构域的结构决定因素提供了值得注意的线索
Both increase and decrease of cardiac inward rectifier current (IK1) are associated with severe cardiac arrhythmias. Flecainide, a widely used antiarrhythmic drug, exhibits ventricular proarrhythmic effects while effectively controlling ventricular arrhythmias associated with mutations in the gene encoding Kir2.1 channels that decrease IK1 (Andersen syndrome). Here we characterize the electrophysiological and molecular basis of the flecainide-induced increase of the current generated by Kir2.1 channels (I-Kir2.1) and IK1 recorded in ventricular myocytes. Flecainide increases outward I-Kir2.1 generated by homotetrameric Kir2.1 channels by decreasing their affinity for intracellular polyamines, which reduces the inward rectification of the current. Flecainide interacts with the HI loop of the cytoplasmic domain of the channel, Cys311 being critical for the effect. This explains why flecainide does not increase IKir2.2 and I-Kir2.3, because Kir2.2 and Kir2.3 channels do not exhibit a Cys residue at the equivalent position. We further show that incubation with flecainide increases expression of functional Kir2.1 channels in themembrane, an effect also determined by Cys311. Indeed, flecainide pharmacologically rescues R67W, but not R218W, channelmutations found in Andersen syndrome patients. Moreover, ourfindings provide noteworthy clues about the structural determinants of the C terminus cytoplasmic domain