title: Modeling analysis of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization under the control of glucagon-like peptide-1 in mouse pancreatic β-cells.
abstract: Glucagon-like peptide-1 (GLP-1) is an intestinally derived blood glucose-lowering hormone that potentiates glucose-stimulated insulin secretion from pancreatic β-cells. The secretagogue action of GLP-1 is explained, at least in part, by its ability to stimulate cAMP production so that cAMP may facilitate the release of Ca(2+) from inositol trisphosphate receptor (IP3R)-regulated Ca(2+) stores. However, a quantitative model has yet to be provided that explains the molecular mechanisms and dynamic processes linking GLP-1-stimulated cAMP production to Ca(2+) mobilization. Here, we performed simulation studies to investigate how GLP-1 alters the abilities of Ca(2+) and IP3 to act as coagonists at IP3R Ca(2+) release channels. A new dynamic model was constructed based on the Kaftan model, which demonstrates dual steady-state allosteric regulation of the IP3R by Ca(2+) and IP3. Data obtained from β-cells were then analyzed to understand how GLP-1 facilitates IP3R-mediated Ca(2+) mobilization when UV flash photolysis is used to uncage Ca(2+) and IP3 intracellularly. When the dynamic model for IP3R activation was incorporated into a minimal cell model, the Ca(2+) transients and oscillations induced by GLP-1 were successfully reconstructed. Simulation studies indicated that transient and oscillatory responses to GLP-1 were produced by sequential positive and negative feedback regulation due to fast activation and slow inhibition of the IP3R by Ca(2+). The slow rate of Ca(2+)-dependent inhibition was revealed to provide a remarkable contribution to the time course of the decay of cytosolic Ca(2+) transients. It also served to drive and pace Ca(2+) oscillations that are significant when evaluating how GLP-1 stimulates insulin secretion.
authors.affiliation: Department of Bioinformatics, College of Life Sciences, Ritsumeikan University, Kusatsu City, Japan; yukari@fc.ritsumei.ac.jp.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Department of Systems Science, Kyoto University, Kyoto, Japan; and.
authors.forename: Takao
authors.initials: T
authors.lastname: Shimayoshi
authors.affiliation: Departments of Medicine and Pharmacology, SUNY Upstate Medical University, Syracuse, New York.
authors.forename: George G
authors.initials: GG
authors.lastname: Holz
authors.affiliation: Department of Bioinformatics, College of Life Sciences, Ritsumeikan University, Kusatsu City, Japan;
authors.forename: Akinori
authors.initials: A
authors.lastname: Noma
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D007328:Insulin; D010446:Peptide Fragments; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D005947:Glucose; D002118:Calcium
keywords: Ca2+ mobilization; glucagon-like peptide-1; inositol 1,4,5-trisphosphate; model stimulation