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

Guoxin Kang, Oleg G. Chepurny, Michael J. Rindler, Leon Collis, Zina Chepurny, Wen Hong Li, Mark Harbeck, Michael W. Roe, George G. Holz

Research output: Contribution to journalArticle

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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 β 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 β 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 β 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 β cell glucose metabolism to stimulate insulin secretion.

Original languageEnglish (US)
Pages (from-to)173-188
Number of pages16
JournalJournal of Physiology
Volume566
Issue number1
DOIs
StatePublished - Jul 1 2005

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Glucagon-Like Peptide 1
Cyclic AMP-Dependent Protein Kinases
Second Messenger Systems
Insulin
Guanine Nucleotide Exchange Factors
Inositol 1,4,5-Trisphosphate Receptors
Ryanodine
Ryanodine Receptor Calcium Release Channel
Thapsigargin
Photolysis
Inositol
Blood Glucose
Heparin
Hormones
Glucose
exenatide

ASJC Scopus subject areas

  • Physiology

Cite this

A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic β cells. / Kang, Guoxin; Chepurny, Oleg G.; Rindler, Michael J.; Collis, Leon; Chepurny, Zina; Li, Wen Hong; Harbeck, Mark; Roe, Michael W.; Holz, George G.

In: Journal of Physiology, Vol. 566, No. 1, 01.07.2005, p. 173-188.

Research output: Contribution to journalArticle

Kang, G, Chepurny, OG, Rindler, MJ, Collis, L, Chepurny, Z, Li, WH, Harbeck, M, Roe, MW & Holz, GG 2005, 'A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic β cells', Journal of Physiology, vol. 566, no. 1, pp. 173-188. https://doi.org/10.1113/jphysiol.2005.087510
Kang, Guoxin ; Chepurny, Oleg G. ; Rindler, Michael J. ; Collis, Leon ; Chepurny, Zina ; Li, Wen Hong ; Harbeck, Mark ; Roe, Michael W. ; Holz, George G. / A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic β cells. In: Journal of Physiology. 2005 ; Vol. 566, No. 1. pp. 173-188.
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