Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels
Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels
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DOI：
10.1073/pnas.111447798
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发表时间：
2001-05-22
影响因子：
11.1
通讯作者：
Slesinger, PA
中科院分区：
文献类型：
--
作者：
Zhou, W;Arrabit, C;Slesinger, PA
局部麻醉剂通常用于治疗心律失常、疼痛和癫痫发作，其对电压门控Na+通道的抑制作用最为人们所知。心血管和中枢神经系统毒性是局部麻醉剂的不良副作用，不能仅归因于Na+通道的抑制。在这里，我们报告，细胞外应用的膜渗透性局部麻醉剂布比卡因选择性抑制G蛋白门控内向整流K+通道（GIRK：Kir 3），但不是其他家庭的内向整流K+通道（ROMK：Kir 1和IRK：Kir 2）。布比卡因抑制GIRK通道在应用的几秒钟内，无论通道是否通过毒蕈碱受体或直接通过共表达的G蛋白G（β γ）亚基激活。布比卡因也抑制酒精诱导的GIRK电流的功能性百日咳毒素敏感的C蛋白的情况下。另一方面，含有来自IRK 1的高亲和力磷脂酰肌醇4，5-二磷酸（PIP 2）结构域的突变GIRK 1和GIRK 2（GIRK 1/2）通道显示布比卡因的抑制作用显著降低。令人惊讶的是，与PIP 2具有高亲和力的GIRK 1/2通道被乙醇抑制，就像IRK 1通道一样。我们提出，膜渗透性局部麻醉剂通过拮抗PIP 2与通道的相互作用来抑制GIRK通道，这对于G（β-γ）和乙醇激活GIRK通道是必需的。
Local anesthetics, commonly used for treating cardiac arrhythmias, pain, and seizures, are best known for their inhibitory effects on voltage-gated Na+ channels. Cardiovascular and central nervous system toxicity are unwanted side-effects from local anesthetics that cannot be attributed to the inhibition of only Na+ channels. Here, we report that extracellular application of the membrane-permeant local anesthetic bupivacaine selectively inhibited G protein-gated inwardly rectifying K+ channels (GIRK:Kir3) but not other families of inwardly rectifying K+ channels (ROMK:Kir1 and IRK:Kir2). Bupivacaine inhibited GIRK channels within seconds of application, regardless of whether channels were activated through the muscarinic receptor or directly via coexpressed G protein G(beta gamma) subunits. Bupivacaine also inhibited alcohol-induced GIRK currents in the absence of functional pertussis toxin-sensitive C proteins. The mutated GIRK1 and GIRK2 (GIRK1/2) channels containing the high-affinity phosphatidylinositol 4,5-bisphosphate (PIP2) domain from IRK1, on the other hand, showed dramatically less inhibition with bupivacaine. Surprisingly, GIRK1/2 channels with high affinity for PIP2 were inhibited by ethanol, like IRK1 channels. We propose that membrane-permeant local anesthetics inhibit GIRK channels by antagonizing the interaction of PIP2 with the channel, which is essential for G(beta gamma) and ethanol activation of GIRK channels.