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首页> 外文期刊>Molecular and Cellular Biology >Hypoxia Triggers AMPK Activation through Reactive Oxygen Species-Mediated Activation of Calcium Release-Activated Calcium Channels
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Hypoxia Triggers AMPK Activation through Reactive Oxygen Species-Mediated Activation of Calcium Release-Activated Calcium Channels

机译：缺氧通过活性氧物种介导的钙释放激活钙通道的激活触发AMPK激活

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AMP-activated protein kinase (AMPK) is an energy sensor activated by increases in [AMP] or by oxidant stress (reactive oxygen species [ROS]). Hypoxia increases cellular ROS signaling, but the pathways underlying subsequent AMPK activation are not known. We tested the hypothesis that hypoxia activates AMPK by ROS-mediated opening of calcium release-activated calcium (CRAC) channels. Hypoxia (1.5% O2) augments cellular ROS as detected by the redox-sensitive green fluorescent protein (roGFP) but does not increase the [AMP]/[ATP] ratio. Increases in intracellular calcium during hypoxia were detected with Fura2 and the calcium-calmodulin fluorescence resonance energy transfer (FRET) sensor YC2.3. Antioxidant treatment or removal of extracellular calcium abrogates hypoxia-induced calcium signaling and subsequent AMPK phosphorylation during hypoxia. Oxidant stress triggers relocation of stromal interaction molecule 1 (STIM1), the endoplasmic reticulum (ER) Ca2+ sensor, to the plasma membrane. Knockdown of STIM1 by short interfering RNA (siRNA) attenuates the calcium responses to hypoxia and subsequent AMPK phosphorylation, while inhibition of L-type calcium channels has no effect. Knockdown of the AMPK upstream kinase LKB1 by siRNA does not prevent AMPK activation during hypoxia, but knockdown of CaMKKβ abolishes the AMPK response. These findings reveal that hypoxia can trigger AMPK activation in the apparent absence of increased [AMP] through ROS-dependent CRAC channel activation, leading to increases in cytosolic calcium that activate the AMPK upstream kinase CaMKKβ.
机译：AMP激活的蛋白激酶（AMPK）是一种能量传感器，可通过[AMP]的增加或氧化应激（活性氧[ROS]）来激活。缺氧会增加细胞ROS信号传导，但随后的AMPK激活所基于的途径尚不清楚。我们测试了以下假设：缺氧通过ROS介导的钙释放激活钙（CRAC）通道的开放来激活AMPK。缺氧（1.5％O 2 ）可以通过氧化还原敏感的绿色荧光蛋白（roGFP）检测到增加细胞ROS，但不会增加[AMP] / [ATP]比。使用Fura2和钙钙调蛋白荧光共振能量转移（FRET）传感器YC2.3检测到了缺氧时细胞内钙的增加。抗氧化剂治疗或去除细胞外钙可消除缺氧引起的钙信号传导，并在缺氧期间随后使AMPK磷酸化。氧化应激触发内质网（ER）Ca 2 + 基质相互作用分子1（STIM1）迁移到质膜。短干扰RNA（siRNA）抑制STIM1减弱了钙对缺氧和随后AMPK磷酸化的反应，而抑制L型钙通道则没有作用。 siRNA敲低AMPK上游激酶LKB1并不能阻止缺氧时AMPK的激活，但敲低CaMKKβ则消除了AMPK反应。这些发现表明，在缺乏通过ROS依赖性CRAC通道激活而增加[AMP]的情况下，低氧可以触发AMPK激活，从而导致激活AMPK上游激酶CaMKKβ的胞浆钙增加。

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