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Role of the Exchange Protein Directly Activated by Cyclic Adenosine 5'-Monophosphate (Epac) Pathway in Regulating Proglucagon Gene Expression in Intestinal Endocrine L Cells

Division of Cell and Molecular Biology (S.L., Z.L., J.S., Y.Z., M.R., D.I., P.W., H.Y.G., T.J.), Toronto General Research Institute, University Health Network; Institute of Medical Science (M.R., T.J.); and Departments of Medicine (P.P.L.L., Y.K., H.Y.G., T.J.), Laboratory Medicine and Pathobiology (S.L., J.S., D.I., T.J.), and Physiology (P.P.L.L., Y.K., H.Y.G., T.J.), University of Toronto, Toronto, Ontario, Canada M5G 2M1

Address all correspondence and requests for reprints to: T. Jin, Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, 67 College Street, Toronto, Ontario, Canada M5G 2M1. E-mail tianru.jin{at}utoronto.ca.

Although proglucagon gene expression and the synthesis of proglucagon encoded peptide hormones could be activated by protein kinase A (PKA) activators such as forskolin/3-isobutyl-1-methylxanthine (IBMX) and cholera toxin, whether the activation is entirely attributed to PKA has not been previously examined. We found that forskolin/IBMX also activate ERK1/2 phosphorylation in intestinal and pancreatic proglucagon-producing cell lines. The MEK inhibitors PD98059 and U0126 were found to repress the expression of proglucagon promoter as well as endogenous proglucagon mRNA in two intestinal proglucagon-producing cell lines and to block the stimulatory effect of forskolin/IBMX on proglucagon mRNA expression. The repressive effect of the PKA-specific inhibitors H-89 and KT-5720, however, was either not observable or much less potent. Forskolin could activate ERK1/2 phosphorylation and proglucagon gene transcription on its own, whereas forskolin plus IBMX are required to effectively activate the PKA pathway in the proglucagon-producing cells. Exchange protein directly activated by cyclic AMP 2 (Epac2, or cAMP-binding guanine nucleotide exchange factor-2) was found to be expressed in gut and pancreatic proglucagon-producing cell lines, whereas the Epac-pathway-specific cAMP analog, 8-pMeOPT-2'O-Me-cAMP, effectively stimulated ERK1/2 phosphorylation as well as proglucagon mRNA expression. We therefore suggest that cAMP at least partially regulates proglucagon gene expression via the Epac-Ras/Rap-Raf-MEK-ERK signaling pathway.

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