Mechanism of action of K channel openers on skeletal muscle KATP channels. Interactions with nucleotides and protons.
Mechanism of action of K channel openers on skeletal muscle KATP channels. Interactions with nucleotides and protons.
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k通道开启器在骨骼肌KATP通道上的作用机理。与核苷酸和质子的相互作用。
DOI：
10.1085/jgp.107.4.489
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发表时间：
1996-04
影响因子：
3.8
通讯作者：
Vivaudou, M
中科院分区：
文献类型：
--
作者：
Forestier, C;Pierrard, J;Vivaudou, M
应用膜片钳技术研究了钾通道开放剂（KCOs）对蛙骨骼肌肌纤维内翻-外翻膜片上KATP通道的作用机制。苯并吡喃KCO（左克罗卡林和SR 47063）打开了部分被ATP、ADP或ATP γ阻断的通道，有和没有Mg 2+，但在不存在内部核苷酸的情况下，即使在通道活性因耗尽而显著下降后，它们也没有作用。因此，KCOs的影响可能仅归因于KCOs和核苷酸之间的竞争性相互作用，正如观察结果所证实的那样，ATP降低了KCOs的表观亲和力，相反，KCOs降低了ATP或ADP的敏感性。质子拮抗的作用，非苯并吡喃KCOs，吡那地尔和阿普卡林，通过提高其解离速率。这种作用类似于酸化对苯并吡喃KCO的作用（Forestier，C.，Y. Depresle和M.维瓦杜FEBS Lett. 325：276-280，1993），这表明，尽管它们的结构多样性，KCO可以通过相同的结合位点起作用。详细分析质子对左克罗卡林或SR 47063诱导的通道活性的抑制作用，发现在100 μ M ATP存在下，这种作用在pH 7和6之间急剧发展，在pH 6.6时达到最大值的一半。这些结果与KATP通道的变构模型定量一致，该通道具有4个质子化位点，2个优先接近Mg（2+）-游离核苷酸的核苷酸位点和1个苯并吡喃KCO位点。该模型的结构影响进行了讨论。
The molecular mechanisms underlying the actions of K channel openers (KCOs) on KATP channels were studied with the patch clamp technique in excised inside-out patches from frog skeletal muscle fibers. Benzopyran KCOs (levcromakalim and SR 47063) opened channels partially blocked by ATP, ADP, or ATP gamma s, with and without Mg2+, but they had no effects in the absence of internal nucleotides, even after channel activity had significantly declined because of rundown. The effects of KCOs could therefore be attributed solely to a competitive interaction between KCOs and nucleotides, as confirmed by observations that ATP decreased the apparent affinity for KCOs and that, conversely, KCOs decreased ATP or ADP sensitivity. Protons antagonized the action of the non-benzopyran KCOs, pinacidil and aprikalim, by enhancing their dissociation rate. This effect resembled the effect of acidification on benzopyran KCOs (Forestier, C., Y. Depresle, and M. Vivaudou. FEBS Lett. 325:276-280, 1993), suggesting that, in spite of their structural diversity, KCOs could act through the same binding sites. Detailed analysis of the inhibitory effects of protons on channel activity induced by levcromakalim or SR 47063 revealed that, in the presence of 100 microM ATP, this effect developed steeply between pH 7 and 6 and was half maximal at pH 6.6. These results are in quantitative agreement with an allosteric model of the KATP channel possessing four protonation sites, two nucleotidic sites accessible preferentially to Mg(2+)-free nucleotides, and one benzopyran KCO site. The structural implications of this model are discussed.
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影响因子：
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作者：
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