Close functional coupling between Ca2+ release-activated Ca2+ channels, arachidonic acid release, and leukotriene C4 secretion
Close functional coupling between Ca2+ release-activated Ca2+ channels, arachidonic acid release, and leukotriene C4 secretion
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DOI：
10.1074/jbc.m403969200
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发表时间：
2004-07-16
影响因子：
4.8
通讯作者：
Parekh, AB
中科院分区：
文献类型：
--
作者：
Chang, WC;Parekh, AB
在非兴奋性细胞中，Ca 2+内流的一个主要途径是通过质膜中的钙库操纵的Ca 2+通道。这些通道通过排空细胞内Ca 2+储存而被激活，并且在某些细胞类型中，特别是造血来源的细胞，通过Ca 2+释放激活的Ca 2+（CRAC）通道发生储存操作的流入。然而，对CRAC通道激活的下游后果知之甚少。在这里，我们报告说，通过CRAC通道的Ca 2+进入刺激花生四烯酸生产，而钙从商店释放是无效的，即使后者引起了一个强大的细胞内Ca 2+信号。我们发现，花生四烯酸释放的Ca 2+进入通过CRAC通道被用来合成强的旁分泌促炎信号白三烯C-4（LTC 4）。CRAC通道的药理学抑制剂和损害CRAC通道活性的线粒体去极化均抑制花生四烯酸释放和LTC 4分泌。因此，花生四烯酸的释放优先刺激subplasmalemmal Ca 2+水平升高，由于开放的CRAC通道，这表明该酶位于靠近CRAC通道。我们的研究结果还确定了CRAC通道的一个新作用，即激活下游信号转导途径，导致LTC 4的分泌。最后，线粒体是通过其对CRAC通道活性的影响产生细胞内（花生四烯酸）和旁分泌（LTC 4）信号的关键决定因素。
In non-excitable cells, one major route for Ca2+ influx is through store-operated Ca2+ channels in the plasma membrane. These channels are activated by the emptying of intracellular Ca2+ stores, and in some cell types, particularly of hemopoietic origin, store-operated influx occurs through Ca2+ release-activated Ca2+ (CRAC) channels. However, little is known about the downstream consequences of CRAC channel activation. Here, we report that Ca2+ entry through CRAC channels stimulates arachidonic acid production, whereas Ca2+ release from the stores is ineffective even though the latter evokes a robust intracellular Ca2+ signal. We find that arachidonic acid released by Ca2+ entering through CRAC channels is used to synthesize the potent paracrine pro-inflammatory signal leukotriene C-4 (LTC4). Both pharmacological inhibitors of CRAC channels and mitochondrial depolarization, which impairs CRAC channel activity, suppress arachidonic acid release and LTC4 secretion. Thus, arachidonic acid release is preferentially stimulated by elevated subplasmalemmal Ca2+ levels due to open CRAC channels, suggesting that the enzyme is located close to the CRAC channels. Our results also identify a novel role for CRAC channels, namely the activation of a downstream signal transduction pathway resulting in the secretion of LTC4. Finally, mitochondria are key determinants of the generation of both intracellular ( arachidonic acid) and paracrine ( LTC4) signals through their effects on CRAC channel activity.