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beta-cell PDE3B regulates Ca2+-stimulated exocytosis of insulin

机译：β细胞PDE3B调节Ca2 +刺激的胰岛素胞吐作用

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cAMP signaling is important for the regulation of insulin secretion in pancreatic beta-cells. The level of intracellular cAMP is controlled through its production by adenylyl cyclases and its breakdown by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE3B is involved in the regulation of nutrient-stimulated insulin secretion. Here, aiming at getting deeper functional insights, we have examined the role of PDE3B in the two phases of insulin secretion as well as its localization in the beta-cell. Depolarization-induced insulin secretion was assessed and in models where PDE3B was overexpressed [islets from transgenic RIP-PDE3B/7 mice and adenovirally (AdPDE3B) infected INS-I (832/13) cells], the first phase of insulin secretion, occurring in response to stimulation with high K+ for 5 min, was significantly reduced (similar to 25% compared to controls). In contrast, in islets from PDE3B(-/-) mice the response to high K+ was increased. Further, stimulation of isolated beta-cells from RIP-PDE3B/7 islets, using successive trains of voltage-clamped depolarizations, resulted in reduced Ca2+-triggered first phase exocytotic response as well as reduced granule mobilization-dependent second phase, compared to wild-type beta-cells. Using sub-cellular fractionation, confocal microscopy and transmission electron microscopy of isolated mouse islets and INS-1 (832/13) cells, we show that endogenous and overexpressed PDE3B is localized to insulin granules and plasma membrane. We conclude that PDE3B, through hydrolysis of cAMP in pools regulated by Ca2+, plays a regulatory role in depolarization-induced insulin secretion and that the enzyme is associated with the exocytotic machinery in beta-cells. (c) 2007 Elsevier Inc. All rights reserved.
机译：cAMP信号对于调节胰岛β细胞中胰岛素的分泌很重要。细胞内cAMP的水平通过腺苷酸环化酶的产生和环核苷酸磷酸二酯酶（PDE）的分解来控制。先前我们已经证明PDE3B参与营养刺激的胰岛素分泌的调节。在这里，为了获得更深入的功能见解，我们检查了PDE3B在胰岛素分泌的两个阶段中的作用及其在β细胞中的定位。评估了去极化诱导的胰岛素分泌，并在过表达PDE3B的模型中[来自转基因RIP-PDE3B / 7小鼠的胰岛和腺病毒（AdPDE3B）感染的INS-1（832/13）细胞]，胰岛素分泌的第一阶段发生在高K +刺激5分钟的反应显着降低（与对照组相比，降低了25％）。相反，在来自PDE3B（-/-）小鼠的胰岛中，对高K +的反应增加了。此外，与野生型相比，使用连续的电压钳制去极化序列刺激从RIP-PDE3B / 7胰岛分离的β细胞，可减少Ca2 +触发的第一相胞吐反应，以及降低的依赖颗粒动员的第二相。输入β细胞。使用分离的小鼠胰岛和INS-1（832/13）细胞的亚细胞分级分离，共聚焦显微镜和透射电镜，我们显示内源性和过表达的PDE3B定位于胰岛素颗粒和质膜。我们得出的结论是，PDE3B通过在由Ca2 +调节的池中水解cAMP，在去极化诱导的胰岛素分泌中起调节作用，并且该酶与β细胞中的胞吐机制有关。 （c）2007 Elsevier Inc.保留所有权利。

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