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Glucagon Stimulates Exocytosis in Mouse and Rat Pancreatic -Cells by Binding to Glucagon Receptors

The Department of Molecular and Cellular Physiology (X.M., Y.Z., A.S., J.V., P.R., L.E.), Diabetes Research Unit, Institute of Physiological Sciences, BMC B11, SE-221 84 Lund, Sweden; Lilly Research Laboratories (J.G., S.S.), Essener Strasse 93, D-22419 Hamburg, Germany; The Rolf Luft Center for Diabetes Research (P.-O.B.), Department of Molecular Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Bartholin Instituttet, Kommunehospitalet (K.B.), DK-1399 Copenhagen K, Denmark; and The Oxford Centre for Diabetes (P.R.), Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Lena Eliasson, The Department of Molecular and Cellular Physiology, Diabetes Research Unit, Institute of Physiological Sciences, Biomedical Center B11 SE-221 84 Lund, Sweden. E-mail: lena.eliasson{at}mphy.lu.se.

Glucagon, secreted by the pancreatic -cells, stimulates insulin secretion from neighboring ß-cells by cAMP- and protein kinase A (PKA)-dependent mechanisms, but it is not known whether glucagon also modulates its own secretion. We have addressed this issue by combining recordings of membrane capacitance (to monitor exocytosis) in individual -cells with biochemical assays of glucagon secretion and cAMP content in intact pancreatic islets, as well as analyses of glucagon receptor expression in pure -cell fractions by RT-PCR. Glucagon stimulated cAMP generation and exocytosis dose dependently with an EC₅₀ of 1.6–1.7 nM. The stimulation of both parameters plateaued at concentrations beyond 10 nM of glucagon where a more than 3-fold enhancement was observed. The actions of glucagon were unaffected by the GLP-1 receptor antagonist exendin-(9-39) but abolished by des-His¹-[Glu⁹]-glucagon-amide, a specific blocker of the glucagon receptor. The effects of glucagon on -cell exocytosis were mimicked by forskolin and the stimulatory actions of glucagon and forskolin on exocytosis were both reproduced by intracellular application of 0.1 mM cAMP. cAMP-potentiated exocytosis involved both PKA-dependent and -independent (resistant to Rp-cAMPS, an Rp-isomer of cAMP) mechanisms. The presence of the cAMP-binding protein cAMP-guanidine nucleotide exchange factor II in -cells was documented by a combination of immunocytochemistry and RT-PCR and 8-(4-chloro-phenylthio)-2'-O-methyl-cAMP, a cAMP-guanidine nucleotide exchange factor II-selective agonist, mimicked the effect of cAMP and augmented rapid exocytosis in a PKA-independent manner. We conclude that glucagon released from the -cells, in addition to its well-documented systemic effects and paracrine actions within the islet, also represents an autocrine regulator of -cell function.

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