title: Epac-selective cAMP analogs: new tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors.
abstract: The identification of 2'-O-methyl substituted adenosine-3',5'-cyclic monophosphate (cAMP) analogs that activate the Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs, also known as Epac1 and Epac2), has ushered in a new era of cyclic nucleotide research in which previously unrecognized signalling properties of the second messenger cAMP have been revealed. These Epac-Selective Cyclic AMP Analogs (ESCAs) incorporate a 2'-O-methyl substitution on the ribose ring of cAMP, a modification that impairs their ability to activate protein kinase A (PKA), while leaving intact their ability to activate Epac (the Exchange Protein directly Activated by Cyclic AMP). One such ESCA in wide-spread use is 8-pCPT-2'-O-Me-cAMP. It is a cell-permeant derivative of 2'-O-Me-cAMP, and it is a super activator of Epac. A wealth of newly published studies demonstrate that 8-pCPT-2'-O-Me-cAMP is a unique tool with which to asses atypical actions of cAMP that are PKA-independent. Particularly intriguing are recent reports demonstrating that ESCAs reproduce the PKA-independent actions of ligands known to stimulate Class I (Family A) and Class II (Family B) GTP-binding protein-coupled receptors (GPCRs). This topical review summarizes the current state of knowledge regarding the molecular pharmacology and signal transduction properties of Epac-selective cAMP analogs. Special attention is focused on the rational drug design of ESCAs in order to improve their Epac selectivity, membrane permeability, and stability. Also emphasized is the usefulness of ESCAs as new tools with which to assess the role of Epac as a determinant of intracellular Ca2+ signalling, ion channel function, neurotransmitter release, and hormone secretion.
authors: Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY, USA. holzg01@popmail.med.nyu.edu
authors: George G
authors: GG
authors: Holz
authors: Oleg G
authors: OG
authors: Chepurny
authors: Frank
authors: F
authors: Schwede
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000032:analysis / Q000502:physiology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases
references: Physiol Rev. 2002 Jul;82(3):769-824
references: 12087135
references: J Biol Chem. 2003 Oct 3;278(40):38548-56
references: 12888551
references: Nat Cell Biol. 2001 Nov;3(11):1020-4
references: 11715024
references: Mol Cell Biol. 2005 Jan;25(1):136-46
references: 15601837
references: Trends Biochem Sci. 2006 Dec;31(12):680-6
references: 17084085
references: EMBO J. 2006 May 17;25(10):2051-61
references: 16642035
references: Mol Cell Biol. 2006 Dec;26(23):9136-47
references: 17000774
references: Biochemistry. 2005 Jun 14;44(23):8312-25
references: 15938621
references: J Reprod Dev. 2007 Feb;53(1):127-33
references: 17077580
references: Am J Physiol Lung Cell Mol Physiol. 2006 Apr;290(4):L710-L722
references: 16284210
references: Pharmacol Rev. 2005 Jun;57(2):279-88
references: 15914470
references: J Physiol. 2005 Sep 15;567(Pt 3):799-813
references: 15994184
references: J Gen Physiol. 2003 Mar;121(3):181-97
references: 12601083
references: Circ Res. 2007 Apr 13;100(7):950-66
references: 17431197
references: Biochem Biophys Res Commun. 2000 Nov 11;278(1):44-7
references: 11071853
references: Nat Rev Mol Cell Biol. 2003 Sep;4(9):733-8
references: 14506476
references: Biochem J. 2004 Sep 15;382(Pt 3):803-10
references: 15202935
references: J Biol Chem. 2003 Sep 12;278(37):35394-402
references: 12819211
references: Prog Nucleic Acid Res Mol Biol. 2002;71:391-444
references: 12102558
references: Pflugers Arch. 2007 Feb;453(5):703-18
references: 16897043
references: J Physiol. 2005 Jul 1;566(Pt 1):173-88
references: 15860526
references: Am J Physiol Endocrinol Metab. 2003 Nov;285(5):E1001-9
references: 14534075
references: Cell Mol Life Sci. 2006 Nov;63(21):2546-53
references: 17058034
references: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2732-6
references: 1313566
references: Physiol Rev. 2004 Jan;84(1):137-67
references: 14715913
references: Biochem J. 2003 Jan 15;369(Pt 2):287-99
references: 12410638
references: J Biol Chem. 2003 Jun 27;278(26):23508-14
references: 12707263
references: J Biol Chem. 2004 Mar 5;279(10):8938-45
references: 14688288
references: Mol Biosyst. 2005 Oct;1(4):325-31
references: 16880999
references: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7
references: 17389385
references: Physiol Rev. 2005 Oct;85(4):1303-42
references: 16183914
references: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16513-8
references: 15545605
references: Mol Endocrinol. 2005 Jan;19(1):198-212
references: 15459251
references: Science. 1998 Dec 18;282(5397):2275-9
references: 9856955
references: Diabetes Metab Res Rev. 2006 Jan-Feb;22(1):64-71
references: 16028217
references: Nat Rev Mol Cell Biol. 2007 Jan;8(1):63-73
references: 17183361
references: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19194-9
references: 17142316
references: J Physiol. 2006 Jun 15;573(Pt 3):595-609
references: 16613879
references: Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):803-8
references: 16407144
references: J Biol Chem. 2001 Dec 7;276(49):46046-53
references: 11598134
references: Mol Pharmacol. 2006 Jan;69(1):374-84
references: 16244178
references: EMBO Rep. 2004 Dec;5(12):1176-80
references: 15550931
references: J Mol Biol. 2004 Mar 19;337(2):355-65
references: 15003452
references: Endocrinology. 2006 Aug;147(8):3727-36
references: 16644915
references: Biochemistry. 2004 May 25;43(20):6091-100
references: 15147193
references: Curr Opin Pharmacol. 2007 Apr;7(2):193-200
references: 17276729
references: Am J Physiol Gastrointest Liver Physiol. 2007 May;292(5):G1403-10
references: 17234888
references: Annu Rev Biochem. 1987;56:615-49
references: 3113327
references: Cell Mol Life Sci. 2006 Jan;63(1):92-9
references: 16378242
references: Diabetes. 2004 Dec;53 Suppl 3:S104-12
references: 15561897
references: J Biol Chem. 2002 Dec 27;277(52):50497-502
references: 12401793
references: J Biol Chem. 2005 Sep 2;280(35):31294-302
references: 15987680
references: J Biol Chem. 2000 Jul 7;275(27):20829-36
references: 10777494
references: Nature. 2005 Sep 22;437(7058):574-8
references: 16177794
references: J Biol Chem. 2006 Aug 4;281(31):21837-21847
references: 16754664
references: J Mol Biol. 2006 Sep 29;362(4):623-39
references: 16934836
references: J Physiol. 2007 Sep 1;583(Pt 2):685-94
references: 17599964
references: J Biol Chem. 2004 Sep 3;279(36):37215-8
references: 15231839
references: J Biol Chem. 2002 May 10;277(19):16805-13
references: 11877431
references: J Biol Chem. 2002 Jul 19;277(29):26581-6
references: 12000763
references: Science. 1995 Aug 11;269(5225):807-13
references: 7638597
references: Am J Physiol Renal Physiol. 2006 Oct;291(4):F882-90
references: 16684923
references: FEBS Lett. 1995 Nov 20;375(3):231-4
references: 7498506
references: Diabetes. 2003 Jan;52(1):124-32
references: 12502502
references: Nat Cell Biol. 2002 Nov;4(11):901-6
references: 12402047
references: J Biol Chem. 2006 Feb 3;281(5):2506-14
references: 16316996
references: Circ Res. 2005 Sep 30;97(7):655-62
references: 16123333
references: FEBS Lett. 2005 Jun 13;579(15):3264-70
references: 15943971
references: Trends Pharmacol Sci. 2005 Nov;26(11):595-602
references: 16183138
references: Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):760-5
references: 9892707
references: FEBS Lett. 2005 Sep 12;579(22):4966-72
references: 16115630
references: J Physiol. 2006 Nov 15;577(Pt 1):5-15
references: 16973695
references: Mol Cell Biol. 2006 Mar;26(6):2130-45
references: 16507992
references: J Mol Biol. 2001 Mar 9;306(5):1167-77
references: 11237625
references: Nat Struct Biol. 2003 Jan;10(1):26-32
references: 12469113
references: J Pharmacol Exp Ther. 2006 Jul;318(1):152-60
references: 16565168
references: Circ Res. 2005 Dec 9;97(12):1296-304
references: 16269655
references: Diabetes. 2004 Dec;53 Suppl 3:S59-62
references: 15561922
references: J Biol Chem. 2004 Feb 27;279(9):7956-61
references: 14660679
references: Biochemistry. 2006 Dec 26;45(51):15318-26
references: 17176054
references: Mol Endocrinol. 2007 Jan;21(1):159-71
references: 17068197
references: Brain Res. 2007 May 11;1145:1-10
references: 17320829
references: Mol Pharmacol. 2006 Jul;70(1):30-40
references: 16569708
references: Mol Cell Biol. 2006 Sep;26(17):6333-46
references: 16914720
references: Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2519-24
references: 17284589
references: J Physiol. 2006 Jan 15;570(Pt 2):271-82
references: 16284079
references: Nature. 2006 Feb 2;439(7076):625-8
references: 16452984
references: Nature. 1998 Dec 3;396(6710):474-7
references: 9853756
references: J Biol Chem. 2007 Feb 23;282(8):5488-95
references: 17178726
references: J Biol Chem. 2006 Mar 31;281(13):8656-66
references: 16407249
references: Diabetes. 2004 Jan;53(1):5-13
references: 14693691
references: J Biol Chem. 2003 Mar 7;278(10):8279-85
references: 12496249
references: Mol Cell. 2004 Jul 23;15(2):279-86
references: 15260978
references: Nature. 2003 Aug 14;424(6950):775-8
references: 12917685
references: Cell Signal. 2007 Jan;19(1):81-6
references: 16839743
references: J Biol Chem. 1983 Sep 10;258(17):10233-9
references: 6309796
references: J Physiol. 2006 Jun 15;573(Pt 3):611-25
references: 16581855
references: J Physiol. 2001 Oct 15;536(Pt 2):375-85
references: 11600673
references: Mol Cell. 2006 Sep 15;23(6):925-31
references: 16973443
references: J Cell Biol. 2003 Feb 17;160(4):487-93
references: 12578910