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

Am J Physiol Cell Physiol. 2007 Dec;293(6):C1924-33. doi: 10.1152/ajpcell.00555.2006. Epub 2007 Oct 10.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Calcium / metabolism*
  • Calcium Signaling / physiology*
  • Cell Line
  • Computational Biology
  • Cyclic AMP / metabolism*
  • Cytoplasm / metabolism
  • GTP-Binding Proteins / metabolism
  • Glucagon-Like Peptide 1 / metabolism
  • Glucose / physiology
  • Incretins / physiology
  • Insulin-Secreting Cells / metabolism*
  • Isoenzymes / metabolism
  • Mice
  • Models, Biological*
  • Phosphoric Diester Hydrolases / metabolism


  • Incretins
  • Isoenzymes
  • Glucagon-Like Peptide 1
  • Cyclic AMP
  • Phosphoric Diester Hydrolases
  • GTP-Binding Proteins
  • Adenylyl Cyclases
  • Glucose
  • Calcium