Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell.
Recently published studies of islet cell function reveal unexpected features of glucagon-like peptide-1 (GLP-1) receptor-mediated signal transduction in the pancreatic beta-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 beta-cells, and downregulation of Epac function diminishes stimulatory effects of GLP-1 on beta-cell Ca(2+) signaling and insulin secretion. Of particular note are new reports demonstrating that Epac couples beta-cell cAMP production to the stimulation of fast Ca(2+)-dependent exocytosis. It is also reported that Epac mediates the cAMP-dependent mobilization of Ca(2+) from intracellular Ca(2+) stores. This is a process of Ca(2+)-induced Ca(2+) release (CICR), and it generates an increase of [Ca(2+)](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 beta-cell stimulus-secretion coupling.
Holz
George G
GG
Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, USA. holzg01@popmail.nyu.edu
D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000502:physiology; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000502:physiology; D005089:Exocytosis; D000067757:Glucagon-Like Peptide-1 Receptor; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D007515:Islets of Langerhans / Q000502:physiology*; D018027:Receptors, Glucagon / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D002352:Carrier Proteins; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; D018027:Receptors, Glucagon; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium