A novel high-affinity inhibitor for inward-rectifier K+ channels
A novel high-affinity inhibitor for inward-rectifier K+ channels
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DOI：
10.1021/bi981178p
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发表时间：
1998-09-22
期刊：
影响因子：
2.9
通讯作者：
Lu, Z
中科院分区：
文献类型：
--
作者：
Jin, WL;Lu, Z
内向整流钾离子通道是一组高度特化的钾离子通道，完成各种重要的生物学任务。内向整流钾离子通道与电压激活钾离子通道不仅在功能上不同，而且在结构上也不同。与电压激活的K+通道相比，内向整流K+通道的四个亚基中的每一个只有两个而不是六个跨膜段。到目前为止，还没有直接靶向任何内向整流K+通道的高亲和力配体。在本研究中，我们确定，纯化和合成的内向整流钾离子通道的蛋白质抑制剂。这种抑制剂被称为tertiapin，以纳摩尔亲和力阻断G蛋白门控通道（GIRK 1/4）和ROMK 1通道，但密切相关的通道IRK 1对tertiapin不敏感。致突变研究表明，特利他平通过结合到离子传导孔的外端来抑制该通道。
Inward-rectifier K+ channels are a group of highly specialized K+ channels that accomplish a variety of important biological tasks. Inward-rectifier K+ channels differ from voltage-activated K+ channels not only functionally but also structurally. Each of the four subunits of the inward-rectifier K+ channels has only two instead of six transmembrane segments compared to the voltage-activated K+ channels. Thus far, there are no high-affinity ligands that directly target any inward-rectifier K+ channel. In the present study, we identified, purified, and synthesized a protein inhibitor of the inward-rectifier K+ channels. The inhibitor, called tertiapin, blocks a G-protein-gated channel (GIRK1/4) and the ROMK1 channel with nanomolar affinities, but a closely related channel, IRK1, is insensitive to tertiapin. Mutagenesis studies show that teritapin inhibits the channel by binding to the external end of the ion conduction pore.