Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by CAMP
Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by CAMP
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DOI：
10.1073/pnas.0707054104
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发表时间：
2007-12-04
影响因子：
11.1
通讯作者：
Seinon, Susumu
中科院分区：
文献类型：
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作者：
Shibasaki, Tadao;Takahashi, Harumi;Seinon, Susumu
CAMP是众所周知的调节各种分泌细胞的胞吐作用，但其确切的作用机制仍不清楚。在这里，我们研究了胰腺β细胞中胰岛素颗粒胞吐过程中cAMP信号的作用。尽管单独激活CAMP信号传导不会导致颗粒与质膜融合，但它明显增强了葡萄糖诱导的融合事件的第一阶段（迅速、显著和短暂的增加）和第二阶段（中度和持续的增加）。有趣的是，所有负责这种增强作用的颗粒都是新招募的，并立即融合到质膜上而不对接（不安分的新来者）。重要的是，在缺乏cAMP结合蛋白Epac 2的小鼠中，葡萄糖诱导的胞吐的第一阶段中cAMP增强的融合事件显著减少（Epac 2（ko/ko））。此外，在胰腺β细胞中通过Epac 2特异性地被cAMP激活的小GTdR Rapt以蛋白激酶A非依赖性方式介导cAMP诱导的胰岛素分泌。我们还开发了一个胰岛素颗粒运动的模拟模型，其中第一相的增强与质膜附近胰岛素颗粒密度的增加相关。综上所述，这些数据表明Epac 2/Rap 1信号传导在CAMP调节胰岛素颗粒动力学中是必不可少的，最有可能是通过控制质膜附近的颗粒密度。
CAMP is well known to regulate exocytosis in various secretory cells, but the precise mechanism of its action remains unknown. Here, we examine the role of CAMP signaling in the exocytotic process of insulin granules in pancreatic beta cells. Although activation of CAMP signaling alone does not cause fusion of the granules to the plasma membrane, it clearly potentiates both the first phase (a prompt, marked, and transient increase) and the second phase (a moderate and sustained increase) of glucose-induced fusion events. Interestingly, all granules responsible for this potentiation are newly recruited and immediately fused to the plasma membrane without docking (restless newcomer). Importantly, cAMP-potentiated fusion events in the first phase of glucose-induced exocytosis are markedly reduced in mice lacking the CAMP-binding protein Epac2 (Epac2(ko/ko)). In addition, the small GTPase Rapt, which is activated by CAMP specifically through Epac2 in pancreatic beta cells, mediates CAMP-induced insulin secretion in a protein kinase A-independent manner. We also have developed a simulation model of insulin granule movement in which potentiation of the first phase is associated with an increase in the insulin granule density near the plasma membrane. Taken together, these data indicate that Epac2/Rap1 signaling is essential in regulation of insulin granule dynamics by CAMP, most likely by controlling granule density near the plasma membrane.