The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion
The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion
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DOI：
10.1074/jbc.274.32.22337
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发表时间：
1999-08-06
影响因子：
4.8
通讯作者：
Michaeli, T
中科院分区：
文献类型：
--
作者：
Han, P;Werber, J;Michaeli, T
为了了解cAMP磷酸二酯酶(PDE)在胰岛素分泌调节中的作用，我们分析了胰腺β细胞系的环核苷酸PDE，并使用家族和同工酶特异性的PDE抑制剂来鉴定能抵消葡萄糖刺激的胰岛素分泌的PDE，我们证明了在βTC3胰岛素瘤细胞中存在可溶性PDE1C、PDE4A和4D(一种cGMP特异性PDE)和颗粒PDE的活性。选择性抑制PDE1C，但不抑制PDE4，以剂量依赖的方式增加葡萄糖刺激的胰岛素分泌，从而证明PDE1C是主要的PDE，对抗βTC3细胞葡萄糖依赖的胰岛素分泌。在胰岛中，抑制PDE1C和PDE3均可增加依赖葡萄糖的胰岛素分泌。βTC3细胞的PDE1C是一种新的同工酶，其cAMP和cGMP的K-m分别为0.47和0.25mM。βTC3细胞的PDE1C同工酶对8-甲氧甲基异丁基甲基黄嘌呤和扎匹司特敏感(IC50分别为7.5和4.5mU/M)，对长春西汀耐药(IC50和100mU/M)，细胞对钙/钙调素的反应明显增强。由于PDE1C对钙/钙调蛋白的反应性和细胞内钙离子的增加，促进了cAMP的降解，从而构成了一种控制胰岛素分泌的葡萄糖依赖的反馈机制。
To understand the role cAMP phosphodiesterases (PDEs) play in the regulation of insulin secretion, we analyzed cyclic nucleotide PDEs of a pancreatic beta-cell line and used family and isozyme-specific PDE inhibitors to identify the PDEs that counteract glucose-stimulated insulin secretion, We demonstrate the presence of soluble PDE1C, PDE4A and 4D, a cGMP-specific PDE, and of particulate PDES, activities in beta TC3 insulinoma cells. Selective inhibition of PDE1C, but not of PDE4, augmented glucose-stimulated insulin secretion in a dose-dependent fashion thus demonstrating that PDE1C is the major PDE counteracting glucose-dependent insulin secretion from beta TC3 cells. In pancreatic islets, inhibition of both PDE1C and PDE3 augmented glucose-dependent insulin secretion. The PDE1C of beta TC3 cells is a novel isozyme possessing a K-m, of 0.47 mu M for cAMP and 0.25 mu M for cGMP. The PDE1C isozyme of beta TC3 cells is sensitive to 8-methoxymethyl isobutylmethylxanthine and zaprinast (IC50 = 7.5 and 4.5 mu M, respectively) and resistant to vinpocetine (IC50 > 100 mu M) Increased responsiveness of PDE1C activity to calcium/calmodulin is evident upon exposure of cells to glucose. Enhanced cAMP degradation by PDE1C, due to increases in its responsiveness to calcium/calmodulin and in intracellular calcium, constitutes a glucose-dependent feedback mechanism for the control of insulin secretion.