Epac:: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic β-cell
Epac:: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic β-cell
复制标题
DOI：
10.2337/diabetes.53.1.5
复制
发表时间：
2004-01-01
期刊：
影响因子：
7.7
通讯作者：
Holz, GG
中科院分区：
文献类型：
--
作者：
Holz, GG
最近发表的关于胰岛细胞功能的研究揭示了胰岛β细胞中高血糖素样多肽-1(GLP-1)受体介导的信号转导的意外特征。尽管GLP-1被证实是cAMP升高因子，但这些研究表明，蛋白激酶A(PKA)并不是GLP-1作用的唯一cAMP结合蛋白。相反，已经描述了另一种cAMP信号机制，其中GLP-1激活被指定为cAMP调节的鸟嘌呤核苷酸交换因子(cAMPGEF，也称为EPAC)的cAMP结合蛋白。EPAC的两个变异体(Epac1和Epac2)在β细胞中表达，下调EPAC功能会减弱GLP-1对β细胞钙信号和胰岛素分泌的刺激作用。特别值得注意的是，新的报告表明，EPAC将β细胞cAMP的产生与快速依赖钙的胞吐作用的刺激相结合。另有报道称，EPAC介导cAMP依赖的细胞内钙库钙动员。这是一个由Ca~(2+)诱导的Ca~(2+)释放(CICR)过程，其产生的[Ca~(2+)]~(2+)升高可能直接刺激线粒体ATP的产生和分泌颗粒的胞吐。本文综述了GLP-1受体介导的信号转导的新发现，并试图确定EPAC和PKA在β细胞刺激-分泌偶联中的相对重要性。
Recently published studies of islet cell function reveal unexpected features of glucagon-like peptide-1 (GLP-1) receptor-mediated signal transduction in the pancreatic beta-cell. Although GLP-1 is established to be a cAMP-elevating agent, these studies demonstrate that protein kinase A (PKA) is not the only cAMP-binding protein by which GLP-1 acts. Instead, an alternative cAMP signaling mechanism has been described, one in which GLP-1 activates cAMP-binding proteins designated as cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac). Two variants of Epac (Epac1 and Epac2) are expressed in beta-cells, and downregulation of Epac function diminishes stimulatory effects of GLP-1 on beta-cell Ca2+ signaling and insulin secretion. Of particular note are new reports demonstrating that Epac couples beta-cell cAMP production to the stimulation of fast Ca2+-dependent exocytosis. It is also reported that Epac mediates the cAMP-dependent mobilization of Ca2+ from intracellular Ca2+ stores. This is a process of Ca2+-induced Ca2+ release (CICR), and it generates an increase of [Ca2+](i) that may serve as a direct stimulus for mitochondrial ATP production and secretory granule exocytosis. This article summarizes new findings concerning GLP-1 receptor-mediated signal transduction and seeks to define the relative importance of Epac and PKA to beta-cell stimulus-secretion coupling.