title: Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic beta-cell: a computational approach.
abstract: 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 (<1 min(-1)) produce low-frequency cAMP oscillations, and faster 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.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. lfridlia@medicine.bsd.uchicago.edu
authors.forename: Leonid E
authors.initials: LE
authors.lastname: Fridlyand
authors.forename: Mark C
authors.initials: MC
authors.lastname: Harbeck
authors.forename: Michael W
authors.initials: MW
authors.lastname: Roe
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D019295:Computational Biology; D000242:Cyclic AMP / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000502:physiology; D054795:Incretins / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism
chemical_list: D054795:Incretins; D007527:Isoenzymes; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D005947:Glucose; D002118:Calcium