The Antimalarial Drug Mefloquine Inhibits Cardiac Inward Rectifier K+ Channels: Evidence for Interference in PIP2-Channel Interaction
The Antimalarial Drug Mefloquine Inhibits Cardiac Inward Rectifier K+ Channels: Evidence for Interference in PIP2-Channel Interaction
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DOI：
10.1097/fjc.0b013e31820b7c03
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发表时间：
2011-04-01
影响因子：
3
通讯作者：
Sanchez-Chapula, Jose A.
中科院分区：
文献类型：
--
作者：
Lopez-Izquierdo, Angelica;Ponce-Balbuena, Daniela;Sanchez-Chapula, Jose A.
抗疟药甲氟喹被发现通过一种未知的机制抑制K-ATP通道。由于甲氟喹是一种阳离子两亲性药物，并且已知可插入脂质双层，因此我们假设甲氟喹干扰PIP 2和Kir通道之间的相互作用，导致通道抑制。我们研究了甲氟喹对HEK-293细胞表达的Kir2.1、Kir2.3、Kir2.3（I213 L）和Kir6.2/SUR 2A通道的抑制作用，以及对猫心肌细胞I-K1和I-KATP的抑制作用。甲氟喹抑制作用的大小顺序为Kir6.2/SUR 2A> Kir2.3（IC_（50）约为2 μ M）> Kir2.1（IC_（50）> 30 μ M）。在心肌细胞中获得了类似的结果。Kir2.3（I213 L）突变体增强了与PIP 2的相互作用强度（与WT相比），其敏感性显著降低（IC 50 = 9 μ M）。在由内向外的贴剂中，连续应用PIP 2显著地阻止了甲氟喹抑制。我们的研究结果支持甲氟喹干扰PIP 2-Kir通道相互作用的想法。
The antimalarial drug mefloquine was found to inhibit the K-ATP channel by an unknown mechanism. Because mefloquine is a Cationic amphiphilic drug and is known to insert into lipid bilayers, we postulate that mefloquine interferes with the interaction between PIP2 and Kir channels resulting in channel inhibition. We studied the inhibitory effects of mefloquine on Kir2.1, Kir2.3, Kir2.3(I213L), and Kir6.2/SUR2A channels expressed in HEK-293 cells, and on I-K1 and I-KATP from feline cardiac myocytes. The order of mefloquine inhibition was Kir6.2/SUR2A approximate to Kir2.3 (IC50 approximate to 2 mu M) > Kir2.1 (IC50 > 30 mu M). Similar results were obtained in cardiac myocytes. The Kir2.3(I213L) mutant, which enhances the strength of interaction with PIP2 (compared to WT), was significantly less sensitive (IC50 = 9 mu M). In inside-out patches, continuous application of PIP2 strikingly prevented the mefloquine inhibition. Our results support the idea that mefloquine interferes with PIP2-Kir channels interactions.