You are hereRecent Publications of Members of the Boston Ithaca Islet Club / A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic beta cells
A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic beta cells
| Title | A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic beta cells |
| Publication Type | Journal Article |
| Year of Publication | 2005 |
| Authors | |
| Journal | J Physiol |
| Volume | 566 |
| Issue | Pt 1 |
| Pagination | 173-88 |
| Date Published | Jul 1 |
| Publication Language | eng |
| ISBN Number | 0022-3751 (Print) |
| Accession Number | 15860526 |
| Key Words | Mice, Inbred C57BL, Male, Islets of Langerhans/*physiology, Guanine Nucleotide Exchange Factors/*metabolism, Glucagon-Like Peptide 1, Glucagon/*metabolism, Cyclic AMP/*metabolism, Cells, Cultured, Receptors, Animals, Protein Precursors/*metabolism, Peptide Fragments/*metabolism, Inositol 1, 4, 5-Trisphosphate Receptors, Cyclic AMP-Dependent Protein Kinases/*metabolism, Ryanodine Receptor Calcium Release Channel/metabolism, Cytoplasmic and Nuclear/metabolism, Calcium Channels/metabolism, Calcium/*metabolism/pharmacology |
| Abstract | 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. |
| Notes | R01-DK45817/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.England |
| URL | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15860526 |
| Citation Key | 394 |
| Export |
- Animals
- Calcium Channels/metabolism
- Calcium/*metabolism/pharmacology
- Cells, Cultured
- Cyclic AMP-Dependent Protein Kinases/*metabolism
- Cyclic AMP/*metabolism
- Glucagon-Like Peptide 1
- Glucagon/*metabolism
- 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