Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic β-cell:: a computational approach
Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic β-cell:: a computational approach
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DOI：
10.1152/ajpcell.00555.2006
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发表时间：
2007-12-01
影响因子：
5.5
通讯作者：
Philipson, Louis H.
中科院分区：
文献类型：
--
作者：
Fridlyand, Leonid E.;Harbeck, Mark C.;Philipson, Louis H.
胰腺 β 细胞中 Ca2+ 和 G 蛋白偶联受体对 cAMP 动力学的调节：一种计算方法。 Am J Physiol Cell Physiol 293：C1924-C1933，2007。首次发表于 2007 年 10 月 10 日； doi：10.1152/ajpcell.00555.2006。 -在本报告中，我们描述了胰腺 β 细胞中 cAMP 动态调节的数学模型。胰高血糖素样肽 1 (GLP-1) 等肠促胰岛素激素可增加胰腺 β 细胞中的 cAMP 并增强胰岛素分泌。在表达基因编码的 cAMP 生物传感器并负载有 fura-2（一种钙指示剂）的 MIN6 胰岛素瘤细胞中进行的成像实验表明，cAMP 振荡受到膜电位和 GLP-1 周期性变化的差异调节。我们模拟了细胞内钙 (Ca2+) 的相互作用及其与钙调蛋白、G 蛋白偶联受体激活、腺苷酸环化酶 (AC) 和磷酸二酯酶 (PDE) 的相互作用。该模型的模拟表明，cAMP 振荡与 β 细胞中的细胞质 Ca2+ 振荡耦合。缓慢的 Ca2+ 振荡 (< 1 min(-1)) 会产生低频 cAMP 振荡，而较快的 Ca2+ 振荡 (> 3-4 min(-1)) 会产生高频、低振幅的 cAMP 振荡。该模型预测 GLP-1 受体激动剂诱导 cAMP 振荡与细胞质 Ca2+ 振荡同相。相反，观察到的反相 Ca2+ 和 cAMP 振荡可以在葡萄糖和四乙铵联合诱导的膜电位变化后进行模拟。该模型为 Ca2+ 依赖性 AC 和 PDE 激活在 Ca2+ 和 cAMP 信号耦合中的关键作用提供了额外的证据。我们的结果揭示了葡萄糖/TEA 和 GLP-1 对 MIN6 β 细胞中 cAMP 动态的影响存在重要差异。
Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic beta-cell: a computational approach. Am J Physiol Cell Physiol 293: C1924-C1933, 2007. First published October 10, 2007; doi: 10.1152/ajpcell.00555.2006. -In this report we describe a mathematical model for the regulation of cAMP dynamics in pancreatic beta-cells. Incretin hormones such as glucagon- like peptide 1 (GLP-1) increase cAMP and augment insulin secretion in pancreatic beta-cells. Imaging experiments performed in MIN6 insulinoma cells expressing a genetically encoded cAMP biosensor and loaded with fura-2, a calcium indicator, showed that cAMP oscillations are differentially regulated by periodic changes in membrane potential and GLP-1. We modeled the interplay of intracellular calcium (Ca2+) and its interaction with calmodulin, G protein- coupled receptor activation, adenylyl cyclases (AC), and phosphodiesterases (PDE). Simulations with the model demonstrate that cAMP oscillations are coupled to cytoplasmic Ca2+ oscillations in the beta-cell. Slow Ca2+ oscillations (< 1 min(-1)) produce low-frequency cAMP oscillations, and faster Ca2+ oscillations (> 3-4 min(-1)) entrain high-frequency, low-amplitude cAMP oscillations. The model predicts that GLP-1 receptor agonists induce cAMP oscillations in phase with cytoplasmic Ca2+ oscillations. In contrast, observed antiphasic Ca2+ and cAMP oscillations can be simulated following combined glucose and tetraethylammonium-induced changes in membrane potential. The model provides additional evidence for a pivotal role for Ca2+-dependent AC and PDE activation in coupling of Ca2+ and cAMP signals. Our results reveal important differences in the effects of glucose/TEA and GLP-1 on cAMP dynamics in MIN6 beta-cells.