title: Regulation of cAMP homeostasis by the efflux protein MRP4 in cardiac myocytes.
abstract: Recent studies indicate that members of the multidrug-resistance protein (MRP) family belonging to ATP binding cassette type C (ABCC) membrane proteins extrude cyclic nucleotides from various cell types. This study aimed to determine whether MRP proteins regulate cardiac cAMP homeostasis. Here, we demonstrate that MRP4 is the predominant isoform present at the plasma membrane of cardiacmyocytes and that it mediates the efflux of cAMP in these cells. MRP4-deficient mice displayed enhanced cardiac myocyte cAMP formation, contractility, and cardiac hypertrophy at 9 mo of age, an effect that was compensated transiently by increased phosphodiesterase expression at young age. These findings suggest that cAMP extrusion via MRP4 acts together with phosphodiesterases to control cAMP levels in cardiac myocytes.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale (INSERM)/Universite Pierre et Marie Curie, Unite Mixte de Recherche en Sante (UMRS) 956, Paris, France.
authors.forename: Yassine
authors.initials: Y
authors.lastname: Sassi
authors.forename: Aniella
authors.initials: A
authors.lastname: Abi-Gerges
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fauconnier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mougenot
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Kobra
authors.initials: K
authors.lastname: Haghighi
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
authors.forename: Stephane N
authors.initials: SN
authors.lastname: Hatem
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lompre
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004452:Echocardiography; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D015056:1-Methyl-3-isobutylxanthine; D000242:Cyclic AMP; D007527:Isoenzymes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; C489540:Abcc4 protein, mouse
references.citation: J Biol Chem. 2011 Mar 4;286(9):6979-88
references.pmid: 21205825
references.citation: Circ Res. 2003 Nov 14;93(10):896-906
references.pmid: 14615493
references.citation: Proc Natl Acad Sci U S A. 2006 May 9;103(19):7500-5
references.pmid: 16648270
references.citation: Gastroenterology. 2011 Apr;140(4):1292-302
references.pmid: 21237168
references.citation: Circ Res. 2006 Oct 13;99(8):816-28
references.pmid: 17038651
references.citation: Diabetes. 2007 Apr;56(4):1136-42
references.pmid: 17229941
references.citation: Drug Metab Rev. 2005;37(1):253-78
references.pmid: 15747503
references.citation: Circ Res. 2006 Nov 10;99(10):1084-91
references.pmid: 17038640
references.citation: Trends Pharmacol Sci. 2008 Apr;29(4):200-7
references.pmid: 18353444
references.citation: J Pharmacol Exp Ther. 2010 Jun;333(3):912-9
references.pmid: 20194529
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):295-9
references.pmid: 8552625
references.citation: Heart Vessels. 2002 Sep;16(6):249-56
references.pmid: 12382034
references.citation: Science. 2002 Mar 1;295(5560):1711-5
references.pmid: 11872839
references.citation: FEBS J. 2007 Jan;274(2):439-50
references.pmid: 17229149
references.citation: J Biol Chem. 1989 Jul 25;264(21):12364-9
references.pmid: 2545708
references.citation: Am J Pathol. 2003 Oct;163(4):1567-77
references.pmid: 14507663
references.citation: Circ Res. 2007 Apr 13;100(7):950-66
references.pmid: 17431197
references.citation: J Clin Invest. 1991 Jul;88(1):15-9
references.pmid: 1647414
references.citation: Nat Rev Mol Cell Biol. 2004 Dec;5(12):959-70
references.pmid: 15573134
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14144-9
references.pmid: 19666481
references.citation: N Engl J Med. 1998 Dec 17;339(25):1810-6
references.pmid: 9854116
references.citation: J Am Soc Nephrol. 2002 Mar;13(3):595-603
references.pmid: 11856762
references.citation: Annu Rev Biochem. 2007;76:481-511
references.pmid: 17376027
references.citation: Circ Res. 2001 Sep 28;89(7):607-13
references.pmid: 11577026
references.citation: Mol Cell Biol. 2004 Sep;24(17):7612-21
references.pmid: 15314169
references.citation: Pflugers Arch. 2007 Feb;453(5):661-73
references.pmid: 16586096
references.citation: N Engl J Med. 1991 Nov 21;325(21):1468-75
references.pmid: 1944425
references.citation: J Biol Chem. 2003 Aug 8;278(32):29509-14
references.pmid: 12764137
references.citation: Annu Rev Physiol. 2002;64:563-94
references.pmid: 11826280
references.citation: Circ Res. 2009 Mar 27;104(6):758-69
references.pmid: 19213956
references.citation: Circ Res. 2008 Apr 25;102(8):959-65
references.pmid: 18323524
references.citation: Circ Res. 2007 Mar 2;100(4):489-501
references.pmid: 17332439
references.citation: J Biol Chem. 2000 Apr 21;275(16):11735-9
references.pmid: 10766795
references.citation: Circ Res. 1996 Apr;78(4):517-24
references.pmid: 8635208
references.citation: J Clin Invest. 2008 Aug;118(8):2747-57
references.pmid: 18636120
references.citation: J Biol Chem. 2001 Nov 9;276(45):42063-9
references.pmid: 11533056
references.citation: Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2111-7
references.pmid: 15626689
references.citation: Indian J Physiol Pharmacol. 1977 Apr-Jun;21(2):133-6
references.pmid: 885598
references.citation: J Physiol. 2007 Aug 1;582(Pt 3):1205-17
references.pmid: 17525113
references.citation: Cell. 2007 Nov 30;131(5):940-51
references.pmid: 18045536
references.citation: FASEB J. 2002 Jan;16(1):99-101
references.pmid: 11772941
references.citation: Nat Clin Pract Cardiovasc Med. 2005 Sep;2(9):475-83
references.pmid: 16265588
references.citation: Pflugers Arch. 2010 Mar;459(4):535-46
references.pmid: 19855995
references.citation: J Clin Invest. 1995 Apr;95(4):1676-83
references.pmid: 7706476
references.citation: Mol Med. 2001 Aug;7(8):509-16
references.pmid: 11591886
references.citation: Lancet. 1998 Aug;352 Suppl 1:SI8-14
references.pmid: 9736474
references.citation: Nature. 1998 Dec 3;396(6710):474-7
references.pmid: 9853756
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: Circ Res. 2009 Oct 9;105(8):784-92
references.pmid: 19745166
references.citation: J Clin Invest. 2011 Jul;121(7):2888-97
references.pmid: 21670499