GLP-1 Inhibits and Adrenaline Stimulates Glucagon Release by Differential Modulation of N- and L-Type Ca2+ Channel-Dependent Exocytosis

Glucagon secretion is inhibited by glucagon-like peptide-1 (GLP-1) and stimulated by adrenaline. These opposing effects on glucagon secretion are mimicked by low (1-10 nM) and high (10 mu M) concentrations of forskolin, respectively. The expression of GLP-1 receptors in a cells is <0.2% of that in beta cells. The GLP-1-induced suppression of glucagon secretion is PKA dependent, is glucose independent, and does not involve paracrine effects mediated by insulin or somatostatin. GLP-1 is without much effect on a cell electrical activity but selectively inhibits N-type Ca2+ channels and exocytosis. Adrenaline stimulates a cell electrical activity, increases [Ca2+] enhances L-type Ca2+ channel activity, and accelerates exocytosis. The stimulatory effect is partially PKA independent and reduced in Epac2-deficient islets. We propose that GLP-1 inhibits glucagon secretion by PKA-dependent inhibition of the N-type Ca2+ channels via a small increase in intracellular cAMP ([cAMP]). Adrenaline stimulates L-type Ca2+ channel-dependent exocytosis by activation of the low-affinity cAMP sensor Epac2 via a large increase in [cAMP],.