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首页> 外文期刊>Molecular and Cellular Biology >Mechanisms of STIM1 Activation of Store-Independent Leukotriene C4-Regulated Ca2+ Channels
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Mechanisms of STIM1 Activation of Store-Independent Leukotriene C4-Regulated Ca2+ Channels

机译：STIM1激活的独立存储的白三烯C4调控的Ca2 +通道的机制。

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We recently showed, in primary vascular smooth muscle cells (VSMCs), that the platelet-derived growth factor activates canonical store-operated Ca2+ entry and Ca2+ release-activated Ca2+ currents encoded by Orai1 and STIM1 genes. However, thrombin activates store-independent Ca2+ selective channels contributed by both Orai3 and Orai1. These store-independent Orai3/Orai1 channels are gated by cytosolic leukotriene C4 (LTC4) and require STIM1 downstream LTC4 action. However, the source of LTC4 and the signaling mechanisms of STIM1 in the activation of this LTC4-regulated Ca2+ (LRC) channel are unknown. Here, we show that upon thrombin stimulation, LTC4 is produced through the sequential activities of phospholipase C, diacylglycerol lipase, 5-lipo-oxygenease, and leukotriene C4 synthase. We show that the endoplasmic reticulum-resident STIM1 is necessary and sufficient for LRC channel activation by thrombin. STIM1 does not form sustained puncta and does not colocalize with Orai1 either under basal conditions or in response to thrombin. However, STIM1 is precoupled to Orai3 and Orai3/Orai1 channels under basal conditions as shown using Forster resonance energy transfer (FRET) imaging. The second coiled-coil domain of STIM1 is required for coupling to either Orai3 or Orai3/Orai1 channels and for LRC channel activation. We conclude that STIM1 employs distinct mechanisms in the activation of store-dependent and store-independent Ca2+ entry pathways.
机译：我们最近发现，在原代血管平滑肌细胞（VSMC）中，血小板衍生的生长因子激活了规范存储操作的Ca 2 + 进入和Ca 2 + 释放-激活由Orai1和STIM1基因编码的Ca 2 + 电流。然而，凝血酶激活了由Orai3和Orai1共同参与的与存储无关的Ca 2 + 选择性通道。这些独立于存储的Orai3 / Orai1通道被胞质白三烯C 4 （LTC 4 ）门控，并需要STIM1下游LTC 4 作用。但是，在激活此LTC 4 调节的Ca 2 + （LRC）通道时，LTC 4 的来源和STIM1的信号传导机制未知。在这里，我们表明在凝血酶刺激下，LTC 4 是通过磷脂酶C，二酰基甘油脂肪酶，5-脂加氧酶和白三烯C 4 合酶的顺序活性而产生的。我们显示内质网驻留STIM1是必要的，并且对于凝血酶激活LRC通道是足够的。在基础条件下或对凝血酶的反应中，STIM1不会形成持续的泪点，也不会与Orai1共定位。但是，如使用Forster共振能量转移（FRET）成像所示，STIM1在基础条件下预耦合到Orai3和Orai3 / Orai1通道。 STIM1的第二个螺旋线圈域是耦合到Orai3或Orai3 / Orai1通道以及激活LRC通道所必需的。我们得出结论，STIM1在激活依赖于存储和独立于存储的Ca 2 + 进入途径中采用了不同的机制。

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