Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria
Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria
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DOI：
10.1161/01.res.0000178451.08719.5b
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发表时间：
2005-08-19
影响因子：
20.1
通讯作者：
Critz, SD
中科院分区：
文献类型：
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作者：
Costa, ADT;Garlid, KD;Critz, SD
细胞内G(I)偶联受体激活包括磷脂酰肌醇3-激酶、内皮型一氧化氮合酶、鸟苷酸环化酶和蛋白激酶G在内的一系列信号通路，从而触发缺血和药物预适应。激活的PKG开放线粒体K-ATP通道(MitoKATP)，从而增加活性氧的产生。PKG和有丝分裂蛋白K(ATP)开放之间的步骤尚不清楚。我们描述了加入纯化的PKG和cGMP对线粒体K+转运的影响。光散射和呼吸测量表明，PKG可诱导心脏、肝脏和脑线粒体中的丝裂原K(ATP)开放，类似于K-ATP通道开放剂二氮卓和克罗卡林。这种作用可被丝裂原激动素(ATP)抑制剂5-羟基癸酸、四苯基膦和格列本脲、PKG选择性抑制剂KT5823和蛋白激酶C(PKC)抑制剂白屈菜碱、Ro318220和PKC-epsilon多肽拮抗剂epsilon V1-2所阻断。MitoK(ATP)是由PKC激活剂12-佛波醇-13-肉豆蔻酸酯打开的。我们认为，PKG是触发途径的胞浆末端成分，它通过一条包括PKC-epsilon的途径将心肌保护信号从胞浆传递到线粒体膜内层。
Ischemic and pharmacological preconditioning can be triggered by an intracellular signaling pathway in which G(i)-coupled surface receptors activate a cascade including phosphatidylinositol 3-kinase, endothelial nitric oxide synthase, guanylyl cyclase, and protein kinase G (PKG). Activated PKG opens mitochondrial K-ATP channels ( mitoKATP) which increase production of reactive oxygen species. Steps between PKG and mitoK(ATP) opening are unknown. We describe effects of adding purified PKG and cGMP on K+ transport in isolated mitochondria. Light scattering and respiration measurements indicate PKG induces opening of mitoK(ATP) similar to K-ATP channel openers like diazoxide and cromakalim in heart, liver, and brain mitochondria. This effect was blocked by mitoK(ATP) inhibitors 5-hydroxydecanoate, tetraphenylphosphonium, and glibenclamide, PKG-selective inhibitor KT5823, and protein kinase C (PKC) inhibitors chelerythrine, Ro318220, and PKC-epsilon peptide antagonist epsilon V1-2. MitoK(ATP) are opened by the PKC activator 12-phorbol 13-myristate acetate. We conclude PKG is the terminal cytosolic component of the trigger pathway; it transmits the cardioprotective signal from cytosol to inner mitochondrial membrane by a pathway that includes PKC-epsilon.