Piccolo, a Ca2+ sensor in pancreatic β-cells -: Involvement of cAMP-GEFII•Rim2•Piccolo complex in cAMP-dependent exocytosis
Piccolo, a Ca2+ sensor in pancreatic β-cells -: Involvement of cAMP-GEFII•Rim2•Piccolo complex in cAMP-dependent exocytosis
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DOI：
10.1074/jbc.m210146200
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发表时间：
2002-12-27
影响因子：
4.8
通讯作者：
Seino, S
中科院分区：
文献类型：
--
作者：
Fujimoto, K;Shibasaki, T;Seino, S
我们先前已经表明，cAMP结合蛋白cAMP-胍核苷酸交换因子II（GEPII）（或Epac 2）与Rim 2相互作用参与胰腺β细胞中cAMP依赖性，蛋白激酶A非依赖性胞吐。cAMP-GEFII. Rim 2复合物的作用需要细胞内cAMP和Ca 2+。虽然Rim 2具有C-2结构域，但其作为Ca 2+传感器的作用仍不清楚。在本研究中，我们发现Piccolo，一种在结构上与Rim 2相关的神经元中的CAZ（（c）在bar下的细胞骨架基质与（a）在bar下的活性（z）在bar下的1）蛋白相关，也与cAMP-GEPII结合，并且它以Ca 2+依赖性方式与Rim 2形成同源二聚体和异源二聚体，而Rim 2单独不形成同源二聚体。Piccolo.Rim2异二聚化的关联比Piccolo.Piccolo同源二聚化强。用Piccolo的反义寡脱氧核苷酸处理胰岛抑制cAMP类似物8-溴环AMP加高糖刺激诱导的胰岛素分泌。这些结果表明Piccolo在胰腺β细胞的胞吐作用中充当Ca 2+传感器，并且cAMP-GEFI I. Rim 2.Piccolo复合物的形成在cAMP诱导的胰岛素分泌中是重要的。此外，这项研究表明，与神经元中的CAZ蛋白类似的CAZ蛋白也在胰腺β细胞中起作用。
We have previously shown that cAMP-binding protein cAMP-guanidine nucleotide exchange factor II (GEFII) (or Epac2) interacting with Rim2 is involved in cAMP-dependent, protein kinase A-independent exocytosis in pancreatic beta-cells. The action of the cAMP-GEFII.Rim2 complex requires both intracellular cAMP and Ca2+. Although Rim2 has C-2 domains, its role as a Ca2+ sensor has remained unclear. In the present investigation, we have discovered that Piccolo, a CAZ ((c) under bar ytoskeletal matrix associated with the (a) under bar ctive (z) under bar one) protein in neurons that is structurally related to Rim2, also binds to cAMP-GEFII and that it forms both homodimer and heterodimer with Rim2 in a Ca2+-dependent manner, whereas Rim2 alone does not form the homodimer. The association of Piccolo.Rim2 heterodimerization is stronger than Piccolo.Piccolo homodimerization. Treatment of pancreatic islets with antisense oligodeoxynucleotides against Piccolo inhibits insulin secretion induced by cAMP analog 8-bromo-cyclic AMP plus high glucose stimulation. These results suggest that Piccolo serves as a Ca2+ sensor in exocytosis in pancreatic beta-cells and that the formation of a cAMP-GEFII.Rim2.Piccolo complex is important in cAMP-induced insulin secretion. In addition, this study suggests that CAZ proteins similar to those in neurons are also function in pancreatic beta-cells.