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This version published online on September 30, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0059
Molecular Endocrinology Vol. 0, No. 2004 200400591-
doi:10.1210/me.2004-0059
Copyright © 2004 by the Endocrine Society.
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Submitted on February 10, 2004
Accepted on September 20, 2004

Glucagon stimulates exocytosis in mouse and rat pancreatic {alpha} cells by binding to glucagon receptors

Xiaosong Ma, Yang Zhang, Jesper Gromada, Sabine Sewing, Per-Olof Berggren, Karsten Buschard, Albert Salehi, Jenny Vikman, Patrik Rorsman, and Lena Eliasson*

The Department of Molecular and Cellular Physiology, Diabetes Research Unit, Institute of Physiological Sciences, BMC B11, SE-221 84 Lund, Sweden; Lilly Research Laboratories, Essener Strasse 93, D-22419 Hamburg, Germany; The Rolf Luft Center for Diabetes Research, Department of Molecular medicine, Karolinska institutet, SE-171 77 Stockholm; Bartholin Instituttet, Kommunehospitalet, DK-1399 Copenhagen K, Denmark; The Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, UK

* To whom correspondence should be addressed. E-mail: lena.eliasson{at}mphy.lu.se.

Glucagon, secreted by the pancreatic {alpha} cells, stimulates insulin secretion from neighboring {beta} cells by cAMP- and 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 {alpha} cells with biochemical assays of glucagon secretion and cAMP content in intact pancreatic islets, as well as analyses of glucagon receptor expression in pure {alpha} 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 a concentrations beyond 10 nM of glucagon where a >3-fold enhancement was observed. The actions of glucagon were unaffected by the GLP-1 receptor antagonist exendin-9 but abolished by des-His1-[Glu9]-glucagon-amide, a specific blocker of the glucagon receptor. The effects of glucagon on {alpha} 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. Cyclic AMP-potentiated exocytosis involved both PKA-dependent and -independent (resistant to Rp-cAMPS) mechanisms. The presence of the cAMP-binding protein cAMP-GEFII in {alpha} cells was documented by a combination of immunocytochemistry and RT-PCR and 8CPT-2Me-cAMP, a cAMP-GEFII-selective agonist, mimicked the effect of cAMP and augmented rapid exocytosis in a PKA-independent manner. We conclude that glucagon released from the {alpha} cells, in addition to its well-documented systemic effects and paracrine actions within the islet, also represents an autocrine regulator of {alpha} cell function.
Key words: Glucagon • exocytosis • cAMP • PKA • cAMP-GEFII • SUR11




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