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

  1. George G. Holz
  1. Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York
  1. Address correspondence and reprint requests to George G. Holz, Associate Professor, Department of Physiology and Neuroscience, Medical Sciences Building, Room 442, 550 First Ave., New York University School of Medicine, New York, NY 10016. E-mail: holzg01{at}popmail.med.nyu.edu

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.

Footnotes

    • Accepted September 25, 2003.
    • Received July 23, 2003.
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