Ca2+ influx through CRAC channels activates cytosolic phospholipase A2, leukotriene C4 secretion, and expression of c-fos through ERK-dependent and -independent pathways in mast cells
Ca2+ influx through CRAC channels activates cytosolic phospholipase A2, leukotriene C4 secretion, and expression of c-fos through ERK-dependent and -independent pathways in mast cells
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DOI：
10.1096/fj.06-6016fje
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发表时间：
2006-11-01
期刊：
影响因子：
4.8
通讯作者：
Parekh, Anant B.
中科院分区：
文献类型：
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作者：
Chang, Wei-Chiao;Nelson, Charmaine;Parekh, Anant B.
胞浆磷脂酶A（2）（cPLA（2））是一种钙离子依赖性酶，在大多数细胞类型中介导激动剂依赖性花生四烯酸释放。然后，花生四烯酸可以被5-脂氧合酶代谢，产生促炎信号白三烯C-4（LTC 4）。在这里，我们报告说，通过钙库操作的CRAC（Ca 2+释放激活的Ca 2+）通道的Ca 2+进入在几分钟内激活细胞外信号调节激酶（ERK），有丝分裂原激活蛋白激酶家族的成员，这是刺激cPLA所必需的（2）。Ca 2+进入通过募集Ca 2+依赖性蛋白激酶C α和β I间接激活ERK。Ca 2+内流还促进胞质5-脂氧合酶向核膜的易位，这是该酶活化的关键步骤。易位依赖于ERK激活。CRAC通道开放导致c-fos转录和翻译增加的发现显示了基因激活的作用。抑制ERK激活不能阻止c-fos表达。我们的研究结果表明，CRAC通道激活通过两种代谢途径（cPLA（2）和5-脂氧合酶）的协同调节产生短期效应，这导致在几分钟内产生细胞内和细胞间信使，以及涉及基因激活的长期变化。这些短期效应是通过ERK介导的，而矛盾的是，c-fos表达不是。因此，通过CRAC通道的Ca 2+内流可以同时激活不同的信号传导途径，最终导致一系列时间上不同的反应。
Cytosolic phospholipase A(2) (cPLA(2)) is a Ca2+-dependent enzyme that mediates agonist-dependent arachidonic acid release in most cell types. Arachidonic acid can then be metabolized by the 5-lipoxygenase enzyme to generate the proinflammatory signal leukotriene C-4 (LTC4). Here we report that Ca2+ entry through store-operated CRAC (Ca2+ release-activated Ca2+) channels activates the extracellular signal-regulated kinases (ERKs), members of the mitogen-activated protein kinase family, within minutes and this is necessary for stimulation of cPLA(2). Ca2+ entry activates ERK indirectly, via recruitment of Ca2+-dependent protein kinase C alpha and beta I. Ca2+ influx also promotes translocation of cytosolic 5-lipoxygenase to the nuclear membrane, a key step in the activation of this enzyme. Translocation is dependent on ERK activation. A role for gene activation is shown by the finding that CRAC channel opening results in increased transcription and translation of c-fos. Inhibition of ERK activation failed to prevent c-fos expression. Our results show that CRAC channel activation elicits short-term effects through the co-coordinated regulation of two metabolic pathways (cPLA(2) and 5-lipoxygenase), which results in the generation of both intra- and intercellular messengers within minutes, as well as longer term changes involving gene activation. These short-term effects are mediated via ERK, whereas, paradoxically, c-fos expression is not. Ca2+ influx through CRAC channels can therefore activate different signaling pathways at the same time, culminating in a range of temporally diverse responses.