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Epac is involved in cAMP-stimulated proglucagon expression and hormone production but not hormone secretion in pancreatic - and intestinal L-cell lines

¹Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network; ²Department of Medicine, ³Department of Physiology, and ⁴Department of Laboratory Medicine and Pathobiology; ⁵Banting and Best Diabetes Centre, Faculty of Medicine, University of Toronto; and ⁶Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

Submitted 6 May 2008 ; accepted in final form 8 October 2008

Both Epac and PKA are effectors of the second messenger cAMP. Utilizing an exchange protein directly activated by cAMP (Epac) pathway-specific cAMP analog (ESCA), we previously reported that Epac signaling regulates proglucagon gene (gcg) expression in the glucagon-like peptide-1 (GLP-1)-producing intestinal endocrine L-cell lines GLUTag and STC-1. We now show that Epac-2 is also expressed in glucagon-producing pancreatic -cell lines, including PKA-deficient InR1-G9 cells, and that ESCA stimulates gcg promoter and mRNA expression in the InR1-G9 cells. Using a dominant-negative Epac-2 expression plasmid (Epac-2DN), we found that Epac inhibition attenuated forskolin-stimulated gcg promoter expression in the PKA-active STC-1 cell line and blocked forskolin-stimulated gcg promoter expression in the InR1-G9 cells. Consistently, ESCA was shown to stimulate glucagon and GLP-1 production in the InR1-G9 and GLUTag cell lines, respectively. Surprisingly, ESCA treatment did not show a notable stimulation of glucagon or GLP-1 secretion from these two cell lines. This is in contrast to its ability to stimulate insulin secretion from the pancreatic INS-1 β-cell line. Our findings suggest that Epac is selectively involved in peptide hormone secretion in pancreatic and intestinal endocrine cells and that distinct signaling cascades are involved in stimulating production vs. secretion of glucagon and GLP-1 in response to cAMP elevation.

glucagon; glucagon-like peptide-1; exchange protein directly activated by adenosine 3',5'-cyclic monophosphate; protein kinase A

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