The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition
The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition
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DOI：
10.1074/jbc.m600959200
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发表时间：
2006-07-28
影响因子：
4.8
通讯作者：
Garlid, Keith D.
中科院分区：
文献类型：
--
作者：
Costa, Alexandre D. T.;Jakob, Regina;Garlid, Keith D.
心肌梗塞是线粒体通透性转变（MPT）开放导致细胞坏死的一种表现。受体介导的心脏保护作用由细胞内信号传导途径触发，包括磷脂酰肌醇 3-激酶、内皮一氧化氮合酶、鸟苷酸环化酶、蛋白激酶 G (PKG) 和线粒体 K-ATP 通道 (mitoKATP)。在这项研究中，我们探索了连接 mitoKATP 和 MPT 的途径。我们证实了之前的发现，即二氮嗪和 PKG 或蛋白激酶 C (PKC) 激活剂抑制 MPT 打开。我们扩展了这些结果并表明其他 K+ 通道开放剂以及 K+ 离子载体缬氨霉素也抑制 MPT 开放，并且这种抑制需要活性氧。通过使用异构体特异性肽，我们发现 K-ATP 通道开放剂、PKG 或缬氨霉素的作用是由 PKC epsilon 介导的。佛波醇 12-肉豆蔻酸酯 13-乙酸酯或 H2O2 激活 PKC epsilon 会导致 MPT 打开的 mitoK(ATP) 独立抑制，而 PKG 或激活的 C 激酶的特异性 PKC epsilon 激动剂 psi e 受体激活 PKC epsilon 会导致 MPT 打开的 mitoK(ATP) 依赖性抑制。外源性 H2O2 抑制 MPT，因为它激活 PKC epsilon，IC50 为 0.4 (+/-0.1) mu M。根据这些结果，我们提出两种不同的 PKC epsilon 库调节该信号通路，一种与 mitoK(ATP) 相关，另一种与 MPT 相关。
Myocardial infarction is a manifestation of necrotic cell death as a result of opening of the mitochondrial permeability transition ( MPT). Receptor-mediated cardioprotection is triggered by an intracellular signaling pathway that includes phosphatidylinositol 3-kinase, endothelial nitric-oxide synthase, guanylyl cyclase, protein kinase G ( PKG), and the mitochondrial K-ATP channel ( mitoKATP). In this study, we explored the pathway that links mitoKATP with the MPT. We confirmed previous findings that diazoxide and activators of PKG or protein kinase C ( PKC) inhibited MPT opening. We extended these results and showed that other K+ channel openers as well as the K+ ionophore valinomycin also inhibited MPT opening and that this inhibition required reactive oxygen species. By using isoform-specific peptides, we found that the effects of K-ATP channel openers, PKG, or valinomycin were mediated by a PKC epsilon. Activation of PKC epsilon by phorbol 12-myristate 13-acetate or H2O2 resulted in mitoK(ATP)-independent inhibition of MPT opening, whereas activation of PKC epsilon by PKG or the specific PKC epsilon agonist psi epsilon receptor for activated C kinase caused mitoK(ATP)-dependent inhibition of MPT opening. Exogenous H2O2 inhibited MPT, because of its activation of PKC epsilon, with an IC50 of 0.4 ( +/- 0.1) mu M. On the basis of these results, we propose that two different PKC epsilon pools regulate this signaling pathway, one in association with mitoK(ATP) and the other in association with MPT.