title: AKAP13 Rho-GEF and PKD-binding domain deficient mice develop normally but have an abnormal response to β-adrenergic-induced cardiac hypertrophy.
abstract: BACKGROUND
  A-kinase anchoring proteins (AKAPs) are scaffolding molecules that coordinate and integrate G-protein signaling events to regulate development, physiology, and disease. One family member, AKAP13, encodes for multiple protein isoforms that contain binding sites for protein kinase A (PKA) and D (PKD) and an active Rho-guanine nucleotide exchange factor (Rho-GEF) domain. In mice, AKAP13 is required for development as null embryos die by embryonic day 10.5 with cardiovascular phenotypes. Additionally, the AKAP13 Rho-GEF and PKD-binding domains mediate cardiomyocyte hypertrophy in cell culture. However, the requirements for the Rho-GEF and PKD-binding domains during development and cardiac hypertrophy are unknown.
  
  
  RESULTS
  To determine if these AKAP13 protein domains are required for development, we used gene-trap events to create mutant mice that lacked the Rho-GEF and/or the protein kinase D-binding domains. Surprisingly, heterozygous matings produced mutant mice at Mendelian ratios that had normal viability and fertility. The adult mutant mice also had normal cardiac structure and electrocardiograms. To determine the role of these domains during β-adrenergic-induced cardiac hypertrophy, we stressed the mice with isoproterenol. We found that heart size was increased similarly in mice lacking the Rho-GEF and PKD-binding domains and wild-type controls. However, the mutant hearts had abnormal cardiac contractility as measured by fractional shortening and ejection fraction.
  
  
  CONCLUSIONS
  These results indicate that the Rho-GEF and PKD-binding domains of AKAP13 are not required for mouse development, normal cardiac architecture, or β-adrenergic-induced cardiac hypertrophic remodeling. However, these domains regulate aspects of β-adrenergic-induced cardiac hypertrophy.
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA. mspindler@gladstone.ucsf.edu
authors: Matthew J
authors: MJ
authors: Spindler
authors: Brian T
authors: BT
authors: Burmeister
authors: Yu
authors: Y
authors: Huang
authors: Edward C
authors: EC
authors: Hsiao
authors: Nathan
authors: N
authors: Salomonis
authors: Mark J
authors: MJ
authors: Scott
authors: Deepak
authors: D
authors: Srivastava
authors: Graeme K
authors: GK
authors: Carnegie
authors: Bruce R
authors: BR
authors: Conklin
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001947:Breeding; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D004562:Electrocardiography; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000196:embryology / Q000503:physiopathology*; D007545:Isoproterenol / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D009200:Myocardial Contraction / Q000187:drug effects*; D009929:Organ Size; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013318:Stroke Volume / Q000187:drug effects*
chemical_list: D054758:A Kinase Anchor Proteins; C526201:Akap13 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D007545:Isoproterenol
references: Methods Mol Biol. 2000;132:365-86
references: 10547847
references: Mol Cell. 2008 Oct 24;32(2):169-79
references: 18951085
references: EMBO J. 2004 Jul 21;23(14):2811-20
references: 15229649
references: Mol Cell. 2004 Sep 24;15(6):889-99
references: 15383279
references: Nat Med. 2001 Sep;7(9):1021-7
references: 11533705
references: J Biol Chem. 2010 Feb 12;285(7):4578-86
references: 20018890
references: Mol Cell Biol. 2006 Dec;26(24):9315-26
references: 17030629
references: Nat Rev Mol Cell Biol. 2004 Dec;5(12):959-70
references: 15573134
references: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12557-62
references: 18711127
references: Circulation. 2008 Mar 18;117(11):1414-22
references: 18316483
references: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3059-63
references: 18287012
references: Proc Natl Acad Sci U S A. 2007 May 15;104(20):8461-6
references: 17485678
references: Genes Dev. 2007 Jun 15;21(12):1559-71
references: 17575056
references: J Biol Chem. 2007 Nov 30;282(48):35308-17
references: 17878165
references: J Biol Chem. 1995 Apr 21;270(16):9327-33
references: 7721854
references: Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20990-5
references: 18093912
references: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D642-8
references: 16381950
references: Clin Exp Med. 2010 Mar;10(1):41-9
references: 19779964
references: J Cell Sci. 2005 Dec 1;118(Pt 23):5637-46
references: 16306226
references: Hum Mol Genet. 2010 Nov 1;19(21):4304-11
references: 20719862
references: Circulation. 2000 Feb 8;101(5):558-69
references: 10662755
references: Eur J Cell Biol. 2006 Jul;85(7):603-10
references: 16460837
references: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1723-8
references: 12578964
references: EMBO J. 1998 Aug 3;17(15):4304-12
references: 9687499
references: Dev Biol. 2004 Dec 15;276(2):253-67
references: 15581863
references: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7
references: 15075390
references: Curr Biol. 2006 Feb 7;16(3):321-7
references: 16461287
references: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9352-7
references: 12077299
references: J Recept Signal Transduct Res. 2008;28(3):265-83
references: 18569527
references: Methods Enzymol. 2000;328:592-615
references: 11075368
references: Methods Enzymol. 2004;390:285-94
references: 15488184
references: Mol Cell Biol. 2004 Oct;24(19):8374-85
references: 15367659
references: Biochem J. 2012 Sep 15;446(3):437-43
references: 22731613
references: J Biol Chem. 2009 Jan 16;284(3):1583-92
references: 18945669
references: Nature. 2005 Sep 22;437(7058):574-8
references: 16177794
references: Histochem J. 2000 Jan;32(1):13-26
references: 10805381
references: Nat Protoc. 2006;1(2):968-71
references: 17406331
references: Science. 1997 May 30;276(5317):1404-7
references: 9162005
references: Oncogene. 1998 May 14;16(19):2513-26
references: 9627117
references: J Biol Chem. 2001 Nov 23;276(47):44247-57
references: 11546812
references: Mech Dev. 2001 Feb;100(2):323-6
references: 11165490
references: J Biol Chem. 2006 Apr 7;281(14):9118-26
references: 16469733
references: J Neurosci. 2007 Jan 10;27(2):355-65
references: 17215396
references: J Biol Chem. 1999 Apr 2;274(14):9760-70
references: 10092665
references: BMC Genomics. 2010 Jan 12;11:25
references: 20067632
references: J Biol Chem. 2010 Apr 16;285(16):12344-54
references: 20139090
references: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10140-5
references: 17537920
references: Carcinogenesis. 2006 Mar;27(3):593-8
references: 16234258
references: Am J Pathol. 2009 May;174(5):1650-62
references: 19395651
references: Circ Res. 2000 Dec 8;87(12):1095-102
references: 11110765
references: Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H1187-92
references: 17028161
references: BMC Genomics. 2007 Mar 29;8:85
references: 17394647
references: J Cell Sci. 1999 Aug;112 ( Pt 16):2725-36
references: 10413680
references: J Biol Chem. 2002 Jul 26;277(30):27294-304
references: 12004056
references: J Cell Sci. 2001 Sep;114(Pt 17):3167-76
references: 11590243
references: Dev Biol. 2010 Jan 15;337(2):432-43
references: 19931525
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D755-61
references: 18996895
references: Physiology (Bethesda). 2009 Apr;24:78-87
references: 19364910
references: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):7059-64
references: 10359838
references: Oncogene. 1994 Feb;9(2):621-8
references: 8290273
references: J Biol Chem. 2012 Nov 23;287(48):40535-46
references: 23045525
references: IUBMB Life. 2009 Apr;61(4):394-406
references: 19319965
references: FEBS Lett. 2001 Nov 2;507(3):264-8
references: 11696353