Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic beta-cell: a computational approach

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 express...

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Veröffentlicht in:American Journal of Physiology: Cell Physiology 2007-12, Vol.293 (6), p.C1924-C1933
Hauptverfasser: Fridlyand, Leonid E, Harbeck, Mark C, Roe, Michael W, Philipson, Louis H
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container_end_page C1933
container_issue 6
container_start_page C1924
container_title American Journal of Physiology: Cell Physiology
container_volume 293
creator Fridlyand, Leonid E
Harbeck, Mark C
Roe, Michael W
Philipson, Louis H
description 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 (Ca(2+)) 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 Ca(2+) oscillations in the beta-cell. Slow Ca(2+) 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 Ca(2+) oscillations. In contrast, observed antiphasic Ca(2+) 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 Ca(2+)-dependent AC and PDE activation in coupling of Ca(2+) and cAMP signals. Our results reveal important differences in the effects of glucose/TEA and GLP-1 on cAMP dynamics in MIN6 beta-cells.
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The model predicts that GLP-1 receptor agonists induce cAMP oscillations in phase with cytoplasmic Ca(2+) oscillations. In contrast, observed antiphasic Ca(2+) 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 Ca(2+)-dependent AC and PDE activation in coupling of Ca(2+) and cAMP signals. 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subjects Adenylyl Cyclases - metabolism
Animals
Calcium - metabolism
Calcium Signaling - physiology
Cell Line
Computational Biology
Cyclic AMP - metabolism
Cytoplasm - metabolism
Glucagon-Like Peptide 1 - metabolism
Glucose - physiology
GTP-Binding Proteins - metabolism
Incretins - physiology
Insulin-Secreting Cells - metabolism
Isoenzymes - metabolism
Mice
Models, Biological
Phosphoric Diester Hydrolases - metabolism
title Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic beta-cell: a computational approach
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