Epac: A New cAMP-Binding Protein in Support of Glucagon-Like Peptide-1 Receptor-Mediated Signal Transduction in the Pancreatic β-Cell

Abstract

Recently published studies of islet cell function reveal unexpected features of glucagon-like peptide-1 (GLP-1) receptor-mediated signal transduction in the pancreatic β-cell. Although GLP-1 is established to be a cAMP-elevating agent, these studies demonstrate that protein kinase A (PKA) is not the only cAMP-binding protein by which GLP-1 acts. Instead, an alternative cAMP signaling mechanism has been described, one in which GLP-1 activates cAMP-binding proteins designated as cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac). Two variants of Epac (Epac1 and Epac2) are expressed in β-cells, and downregulation of Epac function diminishes stimulatory effects of GLP-1 on β-cell Ca2+ signaling and insulin secretion. Of particular note are new reports demonstrating that Epac couples β-cell cAMP production to the stimulation of fast Ca2+-dependent exocytosis. It is also reported that Epac mediates the cAMP-dependent mobilization of Ca2+ from intracellular Ca2+ stores. This is a process of Ca2+-induced Ca2+ release (CICR), and it generates an increase of [Ca2+]i that may serve as a direct stimulus for mitochondrial ATP production and secretory granule exocytosis. This article summarizes new findings concerning GLP-1 receptor-mediated signal transduction and seeks to define the relative importance of Epac and PKA to β-cell stimulus-secretion coupling.