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Endocrinology Vol. 140, No. 9 3919-3927
Copyright © 1999 by The Endocrine Society

ARTICLES

Glucagon-Like Peptide 1 Elevates Cytosolic Calcium in Pancreatic ß-Cells Independently of Protein Kinase A1

Hans-Peter Bode, Birgit Moormann, Regina Dabew and Burkhard Göke

Departments of Gastroenterology and Clinical Research (H.-P.B., B.G.), University of Berne, CH-3010 Berne, Switzerland; Department of Pharmacology (B.M.), Medical School, Philipps University, D-35033 Marburg, Germany; and Clinical Research Unit for Gastrointestinal Endocrinology (R.D.), Department of Medicine, Philipps University, D-35033 Marburg, Germany

Address all correspondence and requests for reprints to: Dr. H.-P. Bode, Departments of Clinical Research and Gastroenterology, University of Berne, Murtenstrasse 35, CH-3010 Berne, Switzerland. E-mail: bode{at}dkf4.unibe.ch

Glucagon-like peptide 1 (7–36)amide (GLP-1) is an insulinotropic intestinal peptide hormone with a potential role as antidiabetogenic therapeutic agent. It mediates a potentiation of glucose-induced insulin secretion, by activation of adenylate cyclase and subsequent elevation of cytosolic free calcium, [Ca2+]cyt. We investigated the role of protein kinase A (PKA) in GLP-1 signal transduction, using isolated mouse islets as well as the differentiated ß-cell line INS-1. Two specific inhibitors of PKA, (Rp)-adenosine cyclic 3',5'-phosporothioate (Rp-cAMPS, up to 3 mM) and KT5720 (up to 10 µM), did not inhibit the GLP-1-induced [Ca2+]cyt elevation. Another PKA inhibitor, H-89, reduced the [Ca2+]cyt elevation only when applied at high concentrations (10–40 µM), higher than sufficient for PKA inhibition in many cell types. Furthermore, at these concentrations, H-89 also inhibited presumably PKA-independent processes such as glucose-induced [Ca2+]cyt elevations and intracellular calcium storage. This suggests a PKA-independent action of H-89. Similarly to H-89, the potent but unselective protein kinase inhibitor staurosporine inhibited the GLP-1-induced [Ca2+]cyt elevation only at high concentrations, at which it also inhibited glucose-induced [Ca2+]cyt elevations. The same observations as with GLP-1 were made when adenylate cyclase was stimulated with forskolin, for selective examination of signal transduction downstream of receptor and G protein. Our results suggest that the GLP-1-induced [Ca2+]cyt elevation is mediated independently of PKA and thus belongs to the yet-little-characterized ensemble of effects that are mediated by binding of cAMP to other target proteins.




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