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首页> 外文期刊>American Journal of Physiology >Intracellular two-phase Ca2+ release and apoptosis controlled by TRP-ML1 channel activity in coronary arterial myocytes
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Intracellular two-phase Ca2+ release and apoptosis controlled by TRP-ML1 channel activity in coronary arterial myocytes

机译：TRP-ML1通道活性控制冠状动脉心肌细胞内细胞内两相Ca2 +的释放和凋亡

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摘要

Activation of the death receptor Fas has been reported to produce a two-phase intracellular Ca2+ release response in coronary arterial myocytes (CAMs), which consists of local Ca2+ bursts via lysosomal transient potential receptor-mucolipin 1 (TRP-ML1) channels and consequent Ca2+ release from the sarcoplasmic reticulum (SR). The present study was designed to explore the molecular mechanism by which lysosomal Ca2+ bursts are coupled with SR Ca2+ release in mouse CAMs and to determine the functional relevance of this lysosome-associated two-phase Ca2+ release to apoptosis, a common action of Fas activation with Fas ligand (FasL). By confocal microscopy, we found that transfection of CAMs with TRP-ML1 small interfering (si)RNA substantially inhibited FasL (10 ng/ml)-induced lysosome Ca2+ bursts and consequent SR Ca2+ release. In contrast, transfection of CAMs with plasmids containing a full-length TRP-ML1 gene enhanced FasL-induced two-phase Ca2+ release. We further demonstrated that FasL significantly increased the colocalization of the lysosomal marker Lamp1 with ryanodine receptor 3 and enhanced a dynamic trafficking of lysosomes to the SR. When CAMs were treated with TRP-ML1 siRNA, FasL-induced interactions between the lysosomes and SR were substantially blocked. Functionally, FasL-induced apoptosis and activation of calpain and calcineurin, the Ca2+ sensitive proteins that mediate apoptosis, were significantly attenuated by silencing TRP-ML1 gene but enhanced by overexpression of TRP-ML1 gene. These results suggest that TRP-ML1 channel-mediated lysosomal Ca2+ bursts upon FasL stimulation promote lysosome trafficking and interactions with the SR, leading to apoptosis of CAMs via a Ca2+-dependent mechanism.
机译：据报道，死亡受体Fas的激活在冠状动脉心肌细胞（CAM）中产生两阶段的细胞内Ca2 +释放反应，该反应由溶酶体瞬时潜在受体-粘蛋白1（TRP-ML1）通道和随后的Ca2 +从肌质网（SR）释放。本研究旨在探索溶酶体Ca2 +爆发与小鼠CAM中SR Ca2 +释放耦合的分子机制，并确定该溶酶体相关的两相Ca2 +释放与细胞凋亡的功能相关性，这是Fas激活与Fas配体（FasL）。通过共聚焦显微镜，我们发现用TRP-ML1小干扰（si）RNA转染CAMs基本上抑制了FasL（10 ng / ml）诱导的溶酶体Ca2 +爆发，并因此释放了SR Ca2 +。相反，用含有全长TRP-ML1基因的质粒转染CAM可以增强FasL诱导的两相Ca2 +释放。我们进一步证明FasL显着增加了溶酶体标记Lamp1与ryanodine受体3的共定位并增强了溶酶体向SR的动态转运。当用TRP-ML1 siRNA处理CAM时，FasL诱导的溶酶体和SR之间的相互作用被基本上阻断了。在功能上，FasL诱导的凋亡和钙蛋白酶和钙调神经磷酸酶（介导细胞凋亡的Ca2 +敏感蛋白）的激活通过沉默TRP-ML1基因而显着减弱，而通过过表达TRP-ML1基因来增强。这些结果表明，FasL刺激后，TRP-ML1通道介导的溶酶体Ca2 +爆发促进了溶酶体运输和与SR的相互作用，从而导致Cas通过依赖Ca2 +的机制发生凋亡。

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