The role of Ca2+ influx in endocytic vacuole formation in pancreatic acinar cells.
The role of Ca2+ influx in endocytic vacuole formation in pancreatic acinar cells.
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DOI：
10.1042/bj20140398
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发表时间：
2015-02-01
期刊：
影响因子：
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通讯作者：
Tepikin AV
中科院分区：
文献类型：
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作者：
Voronina S;Collier D;Chvanov M;Middlehurst B;Beckett AJ;Prior IA;Criddle DN;Begg M;Mikoshiba K;Sutton R;Tepikin AV
急性胰腺炎的诱因会引起细胞内钙离子浓度的持续升高，这是导致胰腺腺泡细胞损伤和最终死亡的原因。空泡化是胰腺腺泡细胞损伤的重要指标。此外，胰蛋白酶原的激活发生在细胞内的空泡中，因此空泡可以被认为是细胞损伤发展过程中的“起始”细胞器。在本研究中，我们探讨了细胞内空泡的形成与急性胰腺炎诱导剂[胆汁酸-牛磺酸-石胆酸-3-硫酸盐(TLC-S)和超最大浓度的胆囊收缩素-8(CCK)]引起的钙内流的关系。我们发现，STIM(间质相互作用分子)/ORAI通道的抑制剂GSK-7975A有效地抑制(由胰腺炎诱导剂刺激的)钙内流和内吞空泡的形成。葛兰素史克-7975A也能抑制TLC-S或CCK诱导的细胞死亡。我们记录了thapsigargin[TG；肌浆/内质网(ER)钙泵抑制剂]诱导的储存操作钙内流(SOCE)引起的细胞内空泡的形成，并观察到GSK-7975A对TG诱导的空泡形成的强烈抑制。最后，我们发现结构无关的钙蛋白酶抑制剂抑制细胞内空泡的形成，这表明这种依赖于钙离子的蛋白水解酶是钙离子升高和细胞内空泡形成之间的中介。内吞液泡是急性胰腺炎发生发展过程中的“始动”细胞器。在本研究中，我们确定了钙库操作的钙内流和钙依赖的蛋白水解酶在这些细胞器的形成中的重要作用。
The inducers of acute pancreatitis trigger a prolonged increase in the cytosolic Ca2+ concentration ([Ca2+]c), which is responsible for the damage to and eventual death of pancreatic acinar cells. Vacuolization is an important indicator of pancreatic acinar cell damage. Furthermore, activation of trypsinogen occurs in the endocytic vacuoles; therefore the vacuoles can be considered as ‘initiating’ organelles in the development of the cell injury. In the present study, we investigated the relationship between the formation of endocytic vacuoles and Ca2+ influx developed in response to the inducers of acute pancreatitis [bile acid taurolithocholic acid 3-sulfate (TLC-S) and supramaximal concentration of cholecystokinin-8 (CCK)]. We found that the inhibitor of STIM (stromal interaction molecule)/Orai channels, GSK-7975A, effectively suppressed both the Ca2+ influx (stimulated by inducers of pancreatitis) and the formation of endocytic vacuoles. Cell death induced by TLC-S or CCK was also inhibited by GSK-7975A. We documented the formation of endocytic vacuoles in response to store-operated Ca2+ entry (SOCE) induced by thapsigargin [TG; inhibitor of sarcoplasmic/endoplasmic reticulum (ER) Ca2+ pumps] and observed strong inhibition of TG-induced vacuole formation by GSK-7975A. Finally, we found that structurally-unrelated inhibitors of calpain suppress formation of endocytic vacuoles, suggesting that this Ca2+-dependent protease is a mediator between Ca2+ elevation and endocytic vacuole formation. Endocytic vacuoles are ‘initiating’ organelles in the development of acute pancreatitis. In the present study, we identified the important roles of store-operated Ca2+ influx and Ca2+-dependent proteases (calpains) in the formation of these organelles.