A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic beta cells

J Physiol. 2005 Jul 1;566(Pt 1):173-88. doi: 10.1113/jphysiol.2005.087510. Epub 2005 Apr 28.


The blood glucose-lowering hormone glucagon-like peptide-1 (GLP-1) stimulates cAMP production, promotes Ca2+ influx, and mobilizes an intracellular source of Ca2+ in pancreatic beta cells. Here we provide evidence that these actions of GLP-1 are functionally related: they reflect a process of Ca2+-induced Ca2+ release (CICR) that requires activation of protein kinase A (PKA) and the Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs). In rat insulin-secreting INS-1 cells or mouse beta cells loaded with caged Ca2+ (NP-EGTA), a GLP-1 receptor agonist (exendin-4) is demonstrated to sensitize intracellular Ca2+ release channels to stimulatory effects of cytosolic Ca2+, thereby allowing CICR to be generated by the uncaging of Ca2+ (UV flash photolysis). This sensitizing action of exendin-4 is diminished by an inhibitor of PKA (H-89) or by overexpression of dominant negative Epac. It is reproduced by cell-permeant cAMP analogues that activate PKA (6-Bnz-cAMP) or Epac (8-pCPT-2'-O-Me-cAMP) selectively. Depletion of Ca2+ stores with thapsigargin abolishes CICR, while inhibitors of Ca2+ release channels (ryanodine and heparin) attenuate CICR in an additive manner. Because the uncaging of Ca2+ fails to stimulate CICR in the absence of cAMP-elevating agents, it is concluded that there exists in beta cells a process of second messenger coincidence detection, whereby intracellular Ca2+ release channels (ryanodine receptors, inositol 1,4,5-trisphosphate (IP3) receptors) monitor a simultaneous increase of cAMP and Ca2+ concentrations. We propose that second messenger coincidence detection of this type may explain how GLP-1 interacts with beta cell glucose metabolism to stimulate insulin secretion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Calcium Channels / metabolism
  • Cells, Cultured
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Glucagon / metabolism*
  • Glucagon-Like Peptide 1
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Inositol 1,4,5-Trisphosphate Receptors
  • Islets of Langerhans / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / metabolism*
  • Protein Precursors / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism


  • Calcium Channels
  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Inositol 1,4,5-Trisphosphate Receptors
  • Peptide Fragments
  • Protein Precursors
  • Receptors, Cytoplasmic and Nuclear
  • Ryanodine Receptor Calcium Release Channel
  • Glucagon-Like Peptide 1
  • Glucagon
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium