Epac 激活剂 8-pCPT-2'-O-Me-cAMP-AM 依赖葡萄糖增强小鼠胰岛胰岛素分泌。
Glucose-dependent potentiation of mouse islet insulin secretion by Epac activator 8-pCPT-2'-O-Me-cAMP-AM.
机构信息
Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, USA.
出版信息
Islets. 2009 Nov-Dec;1(3):260-5. doi: 10.4161/isl.1.3.9645.
Abstract
Epac2 is a cAMP-regulated guanine nucleotide exchange factor (cAMP-GEF) that is proposed to mediate stimulatory actions of the second messenger cAMP on mouse islet insulin secretion. Here we have used methods of islet perifusion to demonstrate that the acetoxymethyl ester (AM-ester) of an Epac-selective cAMP analog (ESCA) penetrates into mouse islets and is capable of potentiating both first and second phases of glucose-stimulated insulin secretion (GSIS). When used at low concentrations (1-10 μM), 8-pCPT-2'-O-Me-cAMP-AM activates Rap1 GTPase but exhibits little or no ability to activate protein kinase A (PKA), as validated in assays of in vitro PKA activity (phosphorylation of Kemptide), Ser (133) CREB phosphorylation status, RIP1-CRE-Luc reporter gene activity, and PKA-dependent AKAR3 biosensor activation. Since quantitative PCR demonstrates Epac2 mRNA to be expressed at levels ca. 5.3-fold greater than that of Epac1, available evidence indicates that Epac2 does in fact mediate stimulatory actions of cAMP on mouse islet GSIS.
摘要
Epac2 是一种 cAMP 调节的鸟嘌呤核苷酸交换因子（cAMP-GEF），据推测它介导第二信使 cAMP 对小鼠胰岛胰岛素分泌的刺激作用。在这里，我们使用胰岛灌流的方法证明，Epac 选择性 cAMP 类似物（ESCA）的乙酰氧甲基酯（AM-ester）能够渗透到小鼠胰岛中，并能够增强葡萄糖刺激的胰岛素分泌（GSIS）的第一和第二阶段。当使用低浓度（1-10 μM）时，8-pCPT-2'-O-Me-cAMP-AM 激活 Rap1 GTPase，但几乎没有或没有能力激活蛋白激酶 A（PKA），如体外 PKA 活性测定（Kemptide 磷酸化）、Ser（133）CREB 磷酸化状态、RIP1-CRE-Luc 报告基因活性和 PKA 依赖性 AKAR3 生物传感器激活所验证。由于定量 PCR 表明 Epac2 mRNA 的表达水平约为 Epac1 的 5.3 倍，现有证据表明 Epac2 确实介导 cAMP 对小鼠胰岛 GSIS 的刺激作用。
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