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

Yukari Takeda, Takao Shimayoshi, George G. Holz, Akinori Noma

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


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 Ca2+from inositol trisphosphate receptor (IP3R)-regulated Ca2+ 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 Ca2+ mobilization. Here, we performed simulation studies to investigate how GLP-1 alters the abilities of Ca2+ and IP3 to act as coagonists at IP3R Ca2+ release channels. A new dynamic model was constructed based on the Kaftan model, which demonstrates dual steady-state allosteric regulation of the IP3R by Ca2+ and IP3. Data obtained from β-cells were then analyzed to understand how GLP-1 facilitates IP3R-mediated Ca2+ mobilization when UV flash photolysis is used to uncage Ca2+ and IP3 intracellularly. When the dynamic model for IP3R activation was incorporated into a minimal cell model, the Ca2+ 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 Ca2+. The slow rate of Ca2+ -dependent inhibition was revealed to provide a remarkable contribution to the time course of the decay of cytosolic Ca2+ transients. It also served to drive and pace Ca2+ oscillations that are significant when evaluating how GLP-1 stimulates insulin secretion.

Original languageEnglish
Pages (from-to)C337-C347
JournalAmerican Journal of Physiology - Cell Physiology
Issue number5
Publication statusPublished - Mar 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology


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