Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C
Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C
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DOI：
10.1161/01.res.83.1.110
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发表时间：
1998-07-13
影响因子：
20.1
通讯作者：
Marbán, E
中科院分区：
文献类型：
--
作者：
Sato, T;O'Rourke, B;Marbán, E
线粒体ATP依赖性K+（mitoK（ATP））通道的药理学开放剂模拟缺血预处理，这种心脏保护作用可被mitoK（ATP）通道阻断剂阻止。蛋白激酶C（PKC）在预适应的诱导和维持中起着关键作用。为了寻找这两组观察结果之间可能的机制联系，我们测量了兔心室肌细胞线粒体基质氧化还原电位作为mitoK（ATP）通道活性的指标。mitoK（ATP）通道开放剂二氮嗪（100 μ mol/L）部分氧化基质氧化还原电位。暴露于佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA，100 nmol/L）加强和加速二氮嗪的作用。PMA的这些作用被mitoK（ATP）通道阻断剂5-羟基癸酸盐阻断，我们在膜电流和黄素蛋白荧光的同时记录中验证了5-羟基癸酸盐是mitoK（ATP）通道的选择性阻断剂。无活性的对照化合物4 α-佛波醇（100 nmol/L）不改变二氮嗪的作用。我们的结论是在完整的心脏细胞中，mitoK（ATP）通道的活性可以由PKC调节。PKC对mitoK（ATP）通道开放的增强作用在缺血预处理的信号转导和靶向ATP依赖性K+通道的药理学心脏保护之间提供了直接的机制联系。
Pharmacological openers of mitochondrial ATP-dependent K+ (mitoK(ATP)) channels mimic ischemic preconditioning, and such cardioprotection can be prevented by mitoK(ATP) channel blockers. It is also known that protein kinase C (PKC) plays a key role in the induction and maintenance of preconditioning, To look for possible mechanistic links between these 2 sets of observations, we measured mitochondrial matrix redox potential as an index of mitoK(ATP) channel activity in rabbit ventricular myocytes. The mitoK(ATP) channel opener diazoxide (100 mu mol/L) partially oxidized the matrix redox potential. Exposure to phorbol 12-myristate 13-acetate (PMA, 100 nmol/L) potentiated and accelerated the effect of diazoxide. These effects of PMA were blocked by the mitoK(ATP) channel blocker 5-hydroxydecanoate, which we verified to be a selective blocker of the mitoK(ATP) channel in simultaneous recordings of membrane current and flavoprotein fluorescence. The inactive control compound 4 alpha-phorbol (100 nmol/L) did not alter the effects of diazoxide, We conclude that the activity of mitoK(ATP) channels can be regulated by PKC in intact heart cells. Potentiation of mitoK(ATP) channel opening by PKC provides a direct mechanistic link between the signal transduction of ischemic preconditioning and pharmacological cardioprotection targeted at ATP-dependent K+ channels.