Expression and Functional Activity of Glucagon, Glucagon-Like Peptide I, and Glucose-Dependent Insulinotropic Peptide Receptors in Rat Pancreatic Islet Cells

Abstract

Rat pancreatic α- and β-cells are critically dependent on hormonal signals generating cyclic AMP (cAMP) as a synergistic messenger for nutrient-induced hormone release. Several peptides of the glucagon-secretin family have been proposed as physiological ligands for cAMP production in β-cells, but their relative importance for islet function is still unknown. The present study shows expression at the RNA level in β-cells of receptors for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide I(7-36) amide (GLP-I), while RNA from islet α-cells hybridized only with GIP receptor cDNA. Western blots confirmed that GLP-I receptors were expressed in β-cells and not in α-cells. Receptor activity, measured as cellular cAMP production after exposing islet β-cells for 15 min to a range of peptide concentrations, was already detected using 10 pmol/l GLP-I and 50 pmol/l GIP but required 1 nmol/l glucagon. EC50 values of GLP-I- and GIP-induced cAMP formation were comparable (0.2 nmol/l) and 45-fold lower than the EC50 of glucagon (9 nmol/l). Maximal stimulation of cAMP production was comparable for the three peptides. In purified α-cells, 1 nmol/l GLP-I failed to increase cAMP levels, while 10 pmol/l to 10 nmol/l GIP exerted similar stimulatory effects as in β-cells. In conclusion, these data show that stimulation of glucagon, GLP-I, and GIP receptors in rat β-cells causes cAMP production required for insulin release, while adenylate cyclase in α-cells is positively regulated by GIP.