Glucagon-like peptide 1 elevates cytosolic calcium in pancreatic beta-cells independently of protein kinase A

Endocrinology. 1999 Sep;140(9):3919-27. doi: 10.1210/endo.140.9.6947.


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 beta-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 microM), 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 microM), 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cell Line
  • Cyclic AMP / physiology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / physiology*
  • Cytosol / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism*
  • Male
  • Mice
  • Mice, Inbred DBA
  • Osmolar Concentration
  • Peptide Fragments / pharmacology*
  • Protein Kinase Inhibitors
  • Protein Precursors / pharmacology*
  • Staurosporine / pharmacology


  • Enzyme Inhibitors
  • Peptide Fragments
  • Protein Kinase Inhibitors
  • Protein Precursors
  • Glucagon-Like Peptide 1
  • Glucagon
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Staurosporine
  • Calcium