title: Cyclic AMP synthesis and hydrolysis in the normal and failing heart.
abstract: Cyclic AMP regulates a multitude of cellular responses and orchestrates a network of intracellular events. In the heart, cAMP is the main second messenger of the β-adrenergic receptor (β-AR) pathway producing positive chronotropic, inotropic, and lusitropic effects during sympathetic stimulation. Whereas short-term stimulation of β-AR/cAMP is beneficial for the heart, chronic activation of this pathway triggers pathological cardiac remodeling, which may ultimately lead to heart failure (HF). Cyclic AMP is controlled by two families of enzymes with opposite actions: adenylyl cyclases, which control cAMP production and phosphodiesterases, which control its degradation. The large number of families and isoforms of these enzymes, their different localization within the cell, and their organization in macromolecular complexes leads to a high level of compartmentation, both in space and time, of cAMP signaling in cardiac myocytes. Here, we review the expression level, molecular characteristics, functional properties, and roles of the different adenylyl cyclase and phosphodiesterase families expressed in heart muscle and the changes that occur in cardiac hypertrophy and failure.
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Guellich
authors.forename: Hind
authors.initials: H
authors.lastname: Mehel
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Fischmeister
mesh_terms: D000262:Adenylyl Cyclases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases
references.citation: Circ Res. 2011 Apr 15;108(8):929-39
references.pmid: 21330599
references.citation: Eur J Pharmacol. 2006 Mar 27;535(1-3):1-12
references.pmid: 16527269
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):295-9
references.pmid: 8552625
references.citation: Biochemistry. 1999 Dec 14;38(50):16706-13
references.pmid: 10600134
references.citation: Nature. 1986 Sep 18-24;323(6085):273-5
references.pmid: 2429189
references.citation: Circ Res. 2013 Jan 18;112(2):289-97
references.pmid: 23168336
references.citation: Cell Metab. 2013 Jun 4;17(6):965-975
references.pmid: 23747252
references.citation: Am J Physiol. 1999 May;276(5):H1699-705
references.pmid: 10330256
references.citation: Circ Res. 2005 Dec 9;97(12):1314-22
references.pmid: 16269653
references.citation: J Am Coll Cardiol. 2006 Aug 1;48(3):559-65
references.pmid: 16875984
references.citation: Hum Gene Ther. 2013 Nov;24(11):937-47
references.pmid: 24164241
references.citation: Basic Res Cardiol. 2011 Mar;106(2):249-62
references.pmid: 21161247
references.citation: Circ Res. 2007 Apr 13;100(7):950-66
references.pmid: 17431197
references.citation: J Biol Chem. 2009 Dec 4;284(49):33824-32
references.pmid: 19801680
references.citation: Circulation. 2007 Oct 16;116(16):1776-83
references.pmid: 17893275
references.citation: Circulation. 2009 Jan 27;119(3):408-16
references.pmid: 19139381
references.citation: Circ Res. 2001 Nov 23;89(11):997-1004
references.pmid: 11717156
references.citation: Circ Res. 2008 May 9;102(9):1091-100
references.pmid: 18369156
references.citation: J Mol Cell Cardiol. 2001 Mar;33(3):561-73
references.pmid: 11181023
references.citation: JAMA. 2013 Mar 27;309(12):1268-77
references.pmid: 23478662
references.citation: Pharmacol Rev. 2006 Sep;58(3):488-520
references.pmid: 16968949
references.citation: Circ Res. 2006 Apr 28;98(8):993-1001
references.pmid: 16645149
references.citation: J Cell Sci. 2014 Mar 1;127(Pt 5):1033-42
references.pmid: 24413164
references.citation: Science. 1989 Jun 30;244(4912):1558-64
references.pmid: 2472670
references.citation: Circ Res. 2013 Jun 7;112(12):1567-76
references.pmid: 23609114
references.citation: Circulation. 2004 Jul 20;110(3):330-6
references.pmid: 15249510
references.citation: J Biol Chem. 2000 Sep 8;275(36):28063-74
references.pmid: 10829034
references.citation: Heart Fail Rev. 2007 Mar;12(1):66-86
references.pmid: 17387610
references.citation: Mol Pharmacol. 2009 Nov;76(5):935-41
references.pmid: 19684092
references.citation: Physiol Rev. 2004 Jan;84(1):137-67
references.pmid: 14715913
references.citation: J Biol Chem. 2002 Oct 11;277(41):38072-8
references.pmid: 12154085
references.citation: Annu Rev Pharmacol Toxicol. 2001;41:145-74
references.pmid: 11264454
references.citation: J Biol Chem. 2010 May 7;285(19):14450-8
references.pmid: 20231277
references.citation: Annu Rev Biochem. 2007;76:481-511
references.pmid: 17376027
references.citation: Neurosignals. 2009;17(1):5-22
references.pmid: 18948702
references.citation: Curr Heart Fail Rep. 2012 Sep;9(3):192-9
references.pmid: 22798047
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):940-5
references.pmid: 12552097
references.citation: J Mol Cell Cardiol. 2012 Feb;52(2):323-9
references.pmid: 21888909
references.citation: EMBO J. 2001 Apr 17;20(8):1921-30
references.pmid: 11296225
references.citation: Circ Res. 2003 Nov 14;93(10):896-906
references.pmid: 14615493
references.citation: Transl Res. 2013 Apr;161(4):313-20
references.pmid: 23261978
references.citation: Trends Cardiovasc Med. 2007 Oct;17(7):215-21
references.pmid: 17936202
references.citation: Basic Res Cardiol. 2008 Jan;103(1):22-30
references.pmid: 18034275
references.citation: J Clin Invest. 1999 Mar;103(6):761-5
references.pmid: 10079095
references.citation: Circ Res. 2004 Jun 11;94(11):1474-82
references.pmid: 15105294
references.citation: Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19778-83
references.pmid: 24248367
references.citation: N Engl J Med. 1991 Nov 21;325(21):1468-75
references.pmid: 1944425
references.citation: PLoS One. 2009 Jun 18;4(6):e5963
references.pmid: 19536287
references.citation: Comp Biochem Physiol A Mol Integr Physiol. 2005 Oct;142(2):136-43
references.pmid: 15927494
references.citation: J Pharmacol Exp Ther. 1993 Jun;265(3):1142-51
references.pmid: 8389853
references.citation: J Biol Chem. 2008 May 23;283(21):14461-8
references.pmid: 18356168
references.citation: PLoS One. 2013 Jul 01;8(7):e68009
references.pmid: 23840883
references.citation: J Biol Chem. 2009 Aug 28;284(35):23540-6
references.pmid: 19574217
references.citation: Circulation. 1997 Nov 4;96(9):3116-23
references.pmid: 9386183
references.citation: Biochem Soc Trans. 2014 Apr;42(2):270-3
references.pmid: 24646229
references.citation: Am J Physiol Heart Circ Physiol. 2012 Feb 1;302(3):H538-43
references.pmid: 22058150
references.citation: Circulation. 2007 Jul 17;116(3):238-48
references.pmid: 17606845
references.citation: J Mol Cell Cardiol. 2012 Feb;52(2):330-40
references.pmid: 21843527
references.citation: Circulation. 2002 Apr 23;105(16):1989-94
references.pmid: 11997288
references.citation: Physiology (Bethesda). 2012 Aug;27(4):248-58
references.pmid: 22875455
references.citation: J Biol Chem. 2007 Nov 9;282(45):32749-57
references.pmid: 17726023
references.citation: Circulation. 2013 Apr 23;127(16):1692-701
references.pmid: 23536361
references.citation: Circulation. 2012 Oct 23;126(17):2073-83
references.pmid: 23008439
references.citation: J Am Coll Cardiol. 2013 Oct 22;62(17):1596-606
references.pmid: 23810893
references.citation: Clin Transl Sci. 2008 Dec;1(3):221-7
references.pmid: 20443853
references.citation: J Biol Chem. 2003 May 9;278(19):16936-40
references.pmid: 12665504
references.citation: J Biol Chem. 2009 Apr 3;284(14):9140-6
references.pmid: 19218243
references.citation: Nature. 2005 Sep 22;437(7058):574-8
references.pmid: 16177794
references.citation: J Physiol. 2001 Jun 1;533(Pt 2):329-40
references.pmid: 11389195
references.citation: Circ Res. 2009 Nov 6;105(10):956-64
references.pmid: 19797176
references.citation: Cell. 2005 Oct 7;123(1):25-35
references.pmid: 16213210
references.citation: Mol Pharmacol. 2011 Mar;79(3):381-8
references.pmid: 21127130
references.citation: J Biol Chem. 2004 May 7;279(19):19955-69
references.pmid: 14981084
references.citation: Circ J. 2009 Feb;73(2):195-200
references.pmid: 19106458
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1990 Dec;342(6):698-705
references.pmid: 1710786
references.citation: J Physiol. 2007 Sep 1;583(Pt 2):685-94
references.pmid: 17599964
references.citation: Circulation. 2005 May 17;111(19):2469-2476
references.pmid: 15867171
references.citation: EMBO Rep. 2013 Mar 1;14(3):276-83
references.pmid: 23381222
references.citation: Cell Metab. 2009 Mar;9(3):265-76
references.pmid: 19254571
references.citation: Circ Res. 2006 Apr 28;98(8):1081-8
references.pmid: 16556871
references.citation: Circ Res. 1994 Jul;75(1):23-32
references.pmid: 8013079
references.citation: J Biol Chem. 2001 Apr 6;276(14):11189-98
references.pmid: 11134006
references.citation: J Biol Chem. 2003 Jul 4;278(27):24461-8
references.pmid: 12711600
references.citation: J Biol Chem. 2005 Jan 21;280(3):1808-16
references.pmid: 15545274
references.citation: Cardiovasc Res. 2004 Jun 1;62(3):450-9
references.pmid: 15158137
references.citation: Drug Discov Today. 2009 Oct;14(19-20):982-91
references.pmid: 19638320
references.citation: EMBO J. 2008 Jan 23;27(2):384-93
references.pmid: 18188154
references.citation: Circulation. 2005 Jun 28;111(25):3342-6
references.pmid: 15983258
references.citation: J Am Coll Cardiol. 2010 Apr 6;55(14):1476-86
references.pmid: 20359598
references.citation: J Biol Chem. 2005 Nov 25;280(47):39168-74
references.pmid: 16172121
references.citation: Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1776-82
references.pmid: 19734365
references.citation: Cell Signal. 2007 Aug;19(8):1765-71
references.pmid: 17482796
references.citation: Circulation. 2006 Aug 1;114(5):388-96
references.pmid: 16864723
references.citation: J Biol Chem. 2004 Dec 10;279(50):52095-105
references.pmid: 15466415
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14771-6
references.pmid: 16186489
references.citation: Science. 1997 Dec 12;278(5345):1907-16
references.pmid: 9417641
references.citation: Mol Cell. 2011 Apr 8;42(1):84-95
references.pmid: 21474070
references.citation: Cell. 2004 Aug 6;118(3):375-87
references.pmid: 15294162
references.citation: Circulation. 1999 Mar 30;99(12):1618-22
references.pmid: 10096940
references.citation: Biochem Biophys Res Commun. 2011 Feb 18;405(3):349-55
references.pmid: 21195051
references.citation: Am J Physiol Heart Circ Physiol. 2010 Sep;299(3):H707-12
references.pmid: 20562336
references.citation: Circ Res. 2005 Dec 9;97(12):1296-304
references.pmid: 16269655
references.citation: J Mol Cell Cardiol. 2010 Feb;48(2):322-30
references.pmid: 19883653
references.citation: Circ Res. 2004 Jul 9;95(1):67-75
references.pmid: 15178638
references.citation: PLoS One. 2010 Dec 03;5(12):e14227
references.pmid: 21151982
references.citation: Circ Res. 2006 Oct 13;99(8):816-28
references.pmid: 17038651
references.citation: Circulation. 2008 Jan 1;117(1):61-9
references.pmid: 18071070
references.citation: Basic Res Cardiol. 2006 Mar;101(2):117-26
references.pmid: 16283593
references.citation: Pharmacol Res. 2004 Mar;49(3):275-81
references.pmid: 14726224
references.citation: Cardiovasc Drugs Ther. 2007 Jun;21(3):171-94
references.pmid: 17373584
references.citation: Science. 2010 Mar 26;327(5973):1653-7
references.pmid: 20185685
references.citation: J Mol Cell Cardiol. 2011 May;50(5):872-83
references.pmid: 21334344
references.citation: J Pharmacol Exp Ther. 2013 Nov;347(2):265-75
references.pmid: 24006339
references.citation: Curr Top Dev Biol. 2005;68:25-48
references.pmid: 16124995
references.citation: Cell. 2007 Jul 27;130(2):247-58
references.pmid: 17662940
references.citation: Physiol Rev. 2011 Apr;91(2):651-90
references.pmid: 21527734
references.citation: J Mol Cell Cardiol. 1995 Sep;27(9):1789-95
references.pmid: 8523440
references.citation: J Am Coll Cardiol. 2008 Apr 15;51(15):1490-7
references.pmid: 18402905
references.citation: J Physiol. 2014 Jan 15;592(2):305-12
references.pmid: 23858012
references.citation: J Mol Cell Cardiol. 2014 Feb;67:38-48
references.pmid: 24345421
references.citation: J Mol Cell Cardiol. 2006 Jul;41(1):170-81
references.pmid: 16750219
references.citation: J Am Coll Cardiol. 2011 May 3;57(18):1846-55
references.pmid: 21527160
references.citation: J Mol Cell Cardiol. 2010 Aug;49(2):330-3
references.pmid: 20353794
references.citation: J Mol Cell Cardiol. 1996 May;28(5):1073-83
references.pmid: 8762044
references.citation: Circ Res. 2003 Aug 22;93(4):364-71
references.pmid: 12869393
references.citation: Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1459-67
references.pmid: 20709863
references.citation: J Am Coll Cardiol. 2012 Jun 12;59(24):2182-90
references.pmid: 22676938
references.citation: J Physiol. 2007 Aug 1;582(Pt 3):1195-203
references.pmid: 17540702
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):437-42
references.pmid: 15625103
references.citation: Biochem J. 2003 Feb 15;370(Pt 1):1-18
references.pmid: 12444918
references.citation: Circ Res. 2006 Nov 10;99(10):1084-91
references.pmid: 17038640
references.citation: Am J Physiol Heart Circ Physiol. 2012 Jun 15;302(12):H2622-8
references.pmid: 22505646
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18225-30
references.pmid: 19828435
references.citation: Br J Pharmacol. 2000 Oct;131(4):811-9
references.pmid: 11030732
references.citation: Biochem J. 2005 Jun 15;388(Pt 3):803-11
references.pmid: 15717866
references.citation: J Biol Chem. 2008 Nov 28;283(48):33527-35
references.pmid: 18838385
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9986-90
references.pmid: 12904575
references.citation: Circ Res. 1991 Apr;68(4):1070-9
references.pmid: 1849058
references.citation: PLoS One. 2013 Sep 16;8(9):e72151
references.pmid: 24147149
references.citation: Cell. 2000 May 12;101(4):365-76
references.pmid: 10830164
references.citation: Pharmacol Ther. 2006 Mar;109(3):366-98
references.pmid: 16102838
references.citation: Nature. 2002 Jan 10;415(6868):198-205
references.pmid: 11805843
references.citation: Cardiovasc Res. 2013 Nov 1;100(2):336-46
references.pmid: 23933582
references.citation: Cell Signal. 2010 Apr;22(4):584-9
references.pmid: 19932173
references.citation: J Mol Cell Cardiol. 2004 Sep;37(3):767-74
references.pmid: 15350849
references.citation: J Clin Invest. 2011 Jul;121(7):2651-61
references.pmid: 21670503
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):7059-64
references.pmid: 10359838
references.citation: Circ Res. 2007 Feb 16;100(3):309-27
references.pmid: 17307970
references.citation: Eur Heart J. 2012 Jul;33(14):1787-847
references.pmid: 22611136
references.citation: Circ Res. 2009 Oct 9;105(8):784-92
references.pmid: 19745166
references.citation: J Mol Cell Cardiol. 2013 Nov;64:11-9
references.pmid: 23988739