Calcium wave propagation in pancreatic acinar cells: functional interaction of inositol 1,4,5-trisphosphate receptors, ryanodine receptors, and mitochondria.
Calcium wave propagation in pancreatic acinar cells: functional interaction of inositol 1,4,5-trisphosphate receptors, ryanodine receptors, and mitochondria.
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DOI：
10.1085/jgp.116.4.547
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发表时间：
2000-10
期刊：
影响因子：
--
通讯作者：
Yule DI
中科院分区：
文献类型：
--
作者：
Straub SV;Giovannucci DR;Yule DI
在胰腺腺泡细胞中，激动剂刺激引起的依赖于肌醇1，4，5-三磷酸(InsP3)的胞浆钙([Ca2+]i)升高起始于顶端的“触发区”，绝大多数InsP3受体(InsP3R)位于该“触发区”。在阈值刺激时，[Ca~(2+)]i信号被限制在这个区域，而当激动剂的浓度最佳地激发分泌时，就会产生一个全局的Ca~(2+)波。简单的钙离子从触发区的扩散不太可能解释全球[钙]i升高。此外，据报道，线粒体的输入限制了钙离子从触发区的扩散。因此，关于局部[Ca~(2+)]i信号如何成为全球反应，尚无共识。因此，这项研究调查了这些事件的机制。抑制线粒体Ca~(2+)输入后，激动剂引起的[Ca~(2+)]i振荡转变为持续性的[Ca~(2+)]_i升高。这些[Ca~(2+)]i的升高依赖于内质网的Ca~(2+)释放，并可被100μ的M ryanodine阻断。同样，在全细胞膜片钳细胞中，生理性[Ca~(2+)]_i水平的“去激活”会导致钙激活电流的快速激活，而这一电流的恢复因线粒体输入的抑制而延长。这种作用也可被兰尼定受体(RyR)阻断而取消。数字成像显示，d-myo InsP3 P4(5)-1-(2-硝基苯基)-乙酯(Cage InsP3)光解产生的局部或整体[Ca~(2+)]i以剂量依赖的方式增加。线粒体抑制允许顶端局部的增加以波的形式在细胞内传播，但这种传播被兰诺定抑制，并且没有看到类似于[Ca~(2+)]i泡芙的最小控制反应。由InsP3引发的全球[钙]i升高也被兰诺定降低，将升高限制在略大于触发区域的区域。这些数据表明，虽然钙释放最初是通过InsP3R触发的，但RyRs的释放是传播全球波的主要机制。此外，线粒体Ca~(2+)输入通过调节RyR激活来控制Ca~(2+)在腺泡细胞中的扩散。
In pancreatic acinar cells, inositol 1,4,5-trisphosphate (InsP3)–dependent cytosolic calcium ([Ca2+]i) increases resulting from agonist stimulation are initiated in an apical “trigger zone,” where the vast majority of InsP3 receptors (InsP3R) are localized. At threshold stimulation, [Ca2+]i signals are confined to this region, whereas at concentrations of agonists that optimally evoke secretion, a global Ca2+ wave results. Simple diffusion of Ca2+ from the trigger zone is unlikely to account for a global [Ca2+]i elevation. Furthermore, mitochondrial import has been reported to limit Ca2+ diffusion from the trigger zone. As such, there is no consensus as to how local [Ca2+]i signals become global responses. This study therefore investigated the mechanism responsible for these events. Agonist-evoked [Ca2+]i oscillations were converted to sustained [Ca2+]i increases after inhibition of mitochondrial Ca2+ import. These [Ca2+]i increases were dependent on Ca2+ release from the endoplasmic reticulum and were blocked by 100 μM ryanodine. Similarly, “uncaging” of physiological [Ca2+]i levels in whole-cell patch-clamped cells resulted in rapid activation of a Ca2+-activated current, the recovery of which was prolonged by inhibition of mitochondrial import. This effect was also abolished by ryanodine receptor (RyR) blockade. Photolysis of d-myo InsP3 P4(5)-1-(2-nitrophenyl)-ethyl ester (caged InsP3) produced either apically localized or global [Ca2+]i increases in a dose-dependent manner, as visualized by digital imaging. Mitochondrial inhibition permitted apically localized increases to propagate throughout the cell as a wave, but this propagation was inhibited by ryanodine and was not seen for minimal control responses resembling [Ca2+]i puffs. Global [Ca2+]i rises initiated by InsP3 were also reduced by ryanodine, limiting the increase to a region slightly larger than the trigger zone. These data suggest that, while Ca2+ release is initially triggered through InsP3R, release by RyRs is the dominant mechanism for propagating global waves. In addition, mitochondrial Ca2+ import controls the spread of Ca2+ throughout acinar cells by modulating RyR activation.
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