Abstract
Epac1 and Epac2 are cyclic nucleotide-binding (CNB) domain containing proteins, which were originally identified as cAMP-regulated guanine nucleotide exchange factors (GEFs) for the small G-protein Rap. Therefore, Epac proteins founded next to protein kinase A (PKA) and cyclic nucleotide-regulated ion channels the third group of cAMP-responsive proteins in higher organisms. Epac proteins are involved in the regulation of several physiological processes. In particular Epac1 mediates the regulation of molecular processes underlying cell adhesion and mobility. In the pancreas activation of Epac2 potentiates the release of glucose-induced insulin secretion and received attention as a putative target for antidiabetic treatment. While the regulation of Epac by cAMP has been analysed in structural and biochemical detail, less is known on the interaction of Epac with non-canonical cyclic nucleotides. This chapter will discuss to what extent other cyclic purines than cAMP or cyclic pyrimidine could act as Epac agonists or antagonists. The focus will be on the biophysical analysis of the interaction between Epac and these cyclic nucleotides.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Adamson RH, Ly JC, Sarai RK, Lenz JF, Altangerel A, Drenckhahn D et al (2008) Epac/Rap1 pathway regulates microvascular hyperpermeability induced by PAF in rat mesentery. Am J Physiol Heart Circ Physiol 294:H1188–H1196
Beckert U, Grundmann M, Wolter S, Schwede F, Rehmann H, Kaever V et al (2014) cNMP-AMs mimic and dissect bacterial nucleotidyl cyclase toxin effects. Biochem Biophys Res Commun 451:497–502
Birukova AA, Zagranichnaya T, Fu P, Alekseeva E, Chen W, Jacobson JR et al (2007) Prostaglandins PGE(2) and PGI(2) promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation. Exp Cell Res 313:2504–2520
Birukova AA, Burdette D, Moldobaeva N, Xing J, Fu P, Birukov KG (2010) Rac GTPase is a hub for protein kinase A and Epac signaling in endothelial barrier protection by cAMP. Microvasc Res 79:128–138
Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129:865–877
Cazorla O, Lucas A, Poirier F, Lacampagne A, Lezoualc'h F (2009) The cAMP binding protein Epac regulates cardiac myofilament function. Proc Natl Acad Sci U S A 106:14144–14149
Cullere X, Shaw SK, Andersson L, Hirahashi J, Luscinskas FW, Mayadas TN (2005) Regulation of vascular endothelial barrier function by Epac, a cAMP-activated exchange factor for Rap GTPase. Blood 105:1950–1955
de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A et al (1998) Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396:474–477
Eliasson L, Ma X, Renstrom E, Barg S, Berggren PO, Galvanovskis J et al (2003) SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic B-cells. J Gen Physiol 121:181–197
Fukuhara S, Sakurai A, Sano H, Yamagishi A, Somekawa S, Takakura N et al (2005) Cyclic AMP potentiates vascular endothelial cadherin-mediated cell–cell contact to enhance endothelial barrier function through an Epac-Rap1 signaling pathway. Mol Cell Biol 25:136–146
Herrmann C (2003) Ras-effector interactions: after one decade. Curr Opin Struct Biol 13:122–129
Huang SK, Wettlaufer SH, Chung J, Peters-Golden M (2008) Prostaglandin E2 inhibits specific lung fibroblast functions via selective actions of PKA and Epac-1. Am J Respir Cell Mol Biol 39:482–489
Idevall-Hagren O, Barg S, Gylfe E, Tengholm A (2010) cAMP mediators of pulsatile insulin secretion from glucose-stimulated single beta-cells. J Biol Chem 285:23007–23018
Kang G, Chepurny OG, Holz GG (2001) cAMP-regulated guanine nucleotide exchange factor II (Epac2) mediates Ca2 + -induced Ca2+ release in INS-1 pancreatic beta-cells. J Physiol 536:375–385
Kang G, Joseph JW, Chepurny OG, Monaco M, Wheeler MB, Bos JL et al (2003) Epac-selective cAMP analog 8-pCPT-2′-O-Me-cAMP as a stimulus for Ca2 + - induced Ca2+ release and exocytosis in pancreatic beta-cells. J Biol Chem 278:8279–8285
Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M et al (1998) A family of cAMP-binding proteins that directly activate Rap1. Science 282:2275–2279
Knox AL, Brown NH (2002) Rap1 GTPase regulation of adherens junction positioning and cell adhesion. Science 295:1285–1288
Kooistra MR, Corada M, Dejana E, Bos JL (2005) Epac1 regulates integrity of endothelial cell junctions through VE-cadherin. FEBS Lett 579:4966–4972
Kraulis PJ (1991) Molscript – a program to produce both detailed and schematic plots of protein structures. J Appl Crystallogr 24:946–950
Li Y, Asuri S, Rebhun JF, Castro AF, Paranavitana NC, Quilliam LA (2006) The RAP1 guanine nucleotide exchange factor Epac2 couples cyclic AMP and Ras signals at the plasma membrane. J Biol Chem 281:2506–2514
Merritt EA, Murphy MEP (1994) Raster3D version-2.0 - A program for photorealistic molecular graphics. Acta Crystallogr D Biol Crystallogr 50:869–873
Metrich M, Lucas A, Gastineau M, Samuel JL, Heymes C, Morel E et al (2008) Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy. Circ Res 102:959–965
Mironov SL, Skorova EY (2011) Stimulation of bursting in pre-Botzinger neurons by Epac through calcium release and modulation of TRPM4 and K-ATP channels. J Neurochem 117:295–308
Mironov SL, Skorova EY, Kugler S (2011) Epac-mediated cAMP-signalling in the mouse model of Rett Syndrome. Neuropharmacology 60:869–877
Morel E, Marcantoni A, Gastineau M, Birkedal R, Rochais F, Garnier A et al (2005) cAMP-binding protein Epac induces cardiomyocyte hypertrophy. Circ Res 97:1296–1304
Murray AJ, Tucker SJ, Shewan DA (2009) cAMP-dependent axon guidance is distinctly regulated by Epac and protein kinase A. J Neurosci 29:15434–15444
Nakamura T, Gold GH (1987) A cyclic nucleotide-gated conductance in olfactory receptor cilia. Nature 325:442–444
Noda K, Zhang J, Fukuhara S, Kunimoto S, Yoshimura M, Mochizuki N (2010) Vascular endothelial-cadherin stabilizes at cell-cell junctions by anchoring to circumferential actin bundles through alpha- and beta-Catenins in cyclic AMP-Epac-Rap1 signal-activated endothelial cells. Mol Biol Cell 21:584–596
Oestreich EA, Wang H, Malik S, Kaproth-Joslin KA, Blaxall BC, Kelley GG et al (2007) Epac-mediated activation of phospholipase C(epsilon) plays a critical role in beta-adrenergic receptor-dependent enhancement of Ca2+ mobilization in cardiac myocytes. J Biol Chem 282:5488–5495
Oestreich EA, Malik S, Goonasekera SA, Blaxall BC, Kelley GG, Dirksen RT et al (2009) Epac and phospholipase Cepsilon regulate Ca2+ release in the heart by activation of protein kinase Cepsilon and calcium-calmodulin kinase II. J Biol Chem 284:1514–1522
Pereira L, Metrich M, Fernandez-Velasco M, Lucas A, Leroy J, Perrier R et al (2007) The cAMP binding protein Epac modulates Ca2+ sparks by a Ca2+/calmodulin kinase signalling pathway in rat cardiac myocytes. J Physiol 583:685–694
Popovic M, Rensen-de LM, Rehmann H (2013) Selectivity of CDC25 homology domain-containing guanine nucleotide exchange factors. J Mol Biol 425:2782–2794
Quilliam LA, Rebhun JF, Castro AF (2002) A growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases. Prog Nucleic Acid Res Mol Biol 71:391–444
Rehmann H (2006) Characterization of the activation of the Rap-specific exchange factor Epac by cyclic nucleotides. Methods Enzymol 407:159–173
Rehmann H, Schwede F, Doskeland SO, Wittinghofer A, Bos JL (2003) Ligand-mediated activation of the cAMP-responsive guanine nucleotide exchange factor Epac. J Biol Chem 278:38548–38556
Rehmann H, Das J, Knipscheer P, Wittinghofer A, Bos JL (2006) Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state. Nature 439:625–628
Rehmann H, Wittinghofer A, Bos JL (2007) Capturing cyclic nucleotides in action: snapshots from crystallographic studies. Nat Rev Mol Cell Biol 8:63–73
Rehmann H, Arias-Palomo E, Hadders MA, Schwede F, Llorca O, Bos JL (2008) Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B. Nature 455:124–127
Schwede F, Bertinetti D, Langerijs CN, Hadders MA, Wienk H, Ellenbroek JH et al (2015) Structure-guided design of selective Epac1 and Epac2 agonists. PLoS Biol 13:e1002038
Scott JD (2006) Compartmentalized cAMP signalling: a personal perspective. Biochem Soc Trans 34:465–467
Shibasaki T, Takahashi H, Miki T, Sunaga Y, Matsumura K, Yamanaka M et al (2007) Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP. Proc Natl Acad Sci U S A 104:19333–19338
Srivastava DP, Woolfrey KM, Jones KA, Anderson CT, Smith KR, Russell TA et al (2012) An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice. PLoS Biol 10:e1001350
Vetter IR, Wittinghofer A (2001) The guanine nucleotide-binding switch in three dimensions. Science 294:1299–1304
Wittchen ES, Worthylake RA, Kelly P, Casey PJ, Quilliam LA, Burridge K (2005) Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function. J Biol Chem 280:11675–11682
Woolfrey KM, Srivastava DP, Photowala H, Yamashita M, Barbolina MV, Cahill ME et al (2009) Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nat Neurosci 12:1275–1284
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Rehmann, H. (2015). Interaction of Epac with Non-canonical Cyclic Nucleotides. In: Seifert, R. (eds) Non-canonical Cyclic Nucleotides. Handbook of Experimental Pharmacology, vol 238. Springer, Cham. https://doi.org/10.1007/164_2015_37
Download citation
DOI: https://doi.org/10.1007/164_2015_37
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-52671-3
Online ISBN: 978-3-319-52673-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)