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 ␤-cell. Although GLP-1 is established to be a cAMPelevating 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 cAMPregulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac). T he insulin secretagogue hormone glucagon-like peptide-1 (GLP-1) and its structurally related peptide analogs NN2211, CJC-1131, and exendin-4 are potent stimulators of the pancreatic ␤-cell GLP-1 receptor (GLP-1-R) (1-4). When administered to type 2 diabetic subjects, these peptides exert multiple antidiabetogenic effects: they stimulate insulin secretion, they lower fasting concentrations of blood glucose, and they attenuate the elevation of blood glucose concentration that is typically observed following ingestion of a meal. Such beneficial blood glucose-lowering actions of GLP-1 indicate a usefulness of the hormone as a new therapeutic agent for the treatment of diabetes. Indeed, efforts are now under way to develop synthetic analogs of GLP-1 that exhibit an optimal pharmacokinetic and pharmacodynamic spectrum of action commensurate with their use as therapeutic agents (1).Simultaneously, efforts have been directed at elucidating the molecular basis for GLP-1-R-mediated signal transduction. Previous studies demonstrate that GLP-1 activates multiple signaling pathways in the ␤-cell (Fig. 1). These pathways include protein kinase A (PKA), Ca 2ϩ / calmodulin-regulated protein kinase (CaMK), mitogenactivated protein kinases (MAPK, ERK1/2), phosphatidylinositol 3-kinase (PI-3K), protein kinase B (PKB, Akt), and atypical protein kinase C-(PKC-). In addition, evidence exists for actions of GLP-1 mediated by protein phosphatase (calcineurin) and hormone-sensitive lipase. Some of these signaling pathways are likely to play an active role in determining the effectiveness of GLP-1 as a stimulus for pancreatic insulin secretion. They may also confer trophic factor-like actions to GLP-1 that underlie its ability to stimulate ␤-cell growth, differentiation, and survival (1).Recent studies of pancreatic ␤-cell stimulus-secretion coupling reveal the existence of an alternative cAMP signal transduction pathway by which GLP-1 may exert its effects (5-12). GLP-1 is shown to stimulate cAMP production, and the action of cAMP is demonstrated to be mediated not only by PKA, but also by a newly recognized family of cAMP-binding proteins designated as cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac) (13,14). Identification of Epac as an intermediary linking the GLP-1-R to the stimulation of insulin secretion has led to an appreciation that the blood glucose-lowering effect of GLP-1 might be reproduced using pharmacological agents that activate cAMP...

Isoform-specific antagonists of exchange proteins directly activated by cAMP

“…Among the two known mammalian EPAC isoforms, EPAC1 is ubiquitously expressed in all major tissues, whereas EPAC2 is mainly restricted to the brain, pancreas, and adrenal gland (1,2). Consistent with this tissue-specific expression pattern of EPAC isoforms, EPAC1 has been implicated in cardiac hypertrophy (3,4), fibrosis (5-7), and cancers (8-10), as well as leptin resistance (11), whereas EPAC2 is involved in diabetes/insulin secretion (12)(13)(14)(15)(16)(17)(18) and autism/depression (19)(20)(21).…”

Mechanisms of action of glucagon-like peptide 1 in the pancreas

“…Expression of a dominant negative Epac 2 (Kang et al, 2001;Kang et al, 2003) or use of Epac 2-directed anti-sense oligonucleotides (Kashima et al, 2001) resulted in a loss of insulin secretion and implicated this isoform of the cAMP exchange protein in the activation of CICR. However the role of Epac 1 in this process has not yet been investigated (Holz, 2004). Confirmation that Epac acts predominantly through the RyR was achieved by pre-incubation of INS-1 cells with ryanodine which resulted in blockage of the 8CPT-2Me-cAMP CICR (Kang et al, 2003).…”

“…The function of Rab3A in insulin exocytosis is very poorly understood and its importance here is in the context of the complex that it forms with Epac2 and Rim2 (Rab3 interacting molecule Ozaki et al, 2000) linking Rim2 with the insulin secretory vesicle (Shibasaki et al, 2004). While generically many actions of Epac are believed to be Rap1 mediated in the specific case of insulin exocytosis there is evidence that Epac2 interacts directly with this granular protein (Holz, 2004). Rab27A was also recently linked to cAMP modulation of insulin vesicle recruitment to the cell membrane and is discussed in greater detail in section 4.7 (Kasai et al, 2005b).…”

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

“…In contrast, PACAP is localized to islet nerve fibers and to the insulin secretory granules (11,29,48,49) and is thought to be involved in neurally-induced islet effects also in the presence of lower and more basal plasma glucose concentrations just as, e.g., during the cephalic phase of insulin secretion as well as in other situations of increased neural activity in the islets. Moreover, the effects of both GLP-1 and PACAP seem to be strongly related to cyclic AMP generation, although they use different types of G protein-coupled receptors (11,12,17,19,43), and GLP-1 has been shown to activate a multitude of other signaling pathways in the ␤-cells (17), whereas the effects of PACAP are currently less well understood and more controversial …”