title: Phosphatidylinositol 4,5-bisphosphate regulates CapZβ1 and actin dynamics in response to mechanical strain.
abstract: Mechanical stress causes filament remodeling leading to myocyte hypertrophy and heart failure. The actin capping protein Z (CapZ) tightly binds to the barbed end of actin filaments, thus regulating actin assembly. The hypothesis is that the binding between CapZ and the actin filament is modulated through phosphatidylinositol 4,5-bisphosphate (PIP2) and how the COOH-terminus of CapZβ1 regulates this binding. Primary neonatal rat ventricular myocytes (NRVMs) were strained at 10% amplitude and 1-Hz frequency. Dot blotting measured the PIP2 amount, and affinity precipitation assay assessed the direct interaction between PIP2 and CapZβ1. Fluorescence recovery after photobleaching of green fluorescent protein-CapZβ1 and actin-green fluorescent protein after 1 h of strain shows the dynamics significantly increased above the unstrained group. The increases in CapZ and actin dynamics were blunted by neomycin, suggesting PIP2 signaling is involved. The amount of PIP2 dramatically increased in NRVMs strained for 1 h. With a ROCK or RhoA inhibitor, changes were markedly reduced. Subcellular fractionation and antibody localization showed PIP2 distributed to the sarcomeres. More PIP2-bound CapZβ1 was found in strained NRVMs. Less PIP2 bound to the CapZβ1 with its COOH-terminus intact than in the COOH-terminal mutant of CapZβ1, suggesting some inhibitory role for the COOH-terminus. Myocyte hypertrophy normally induced by 48 h of cyclic strain was blunted by dominant negative RhoA or neomycin. This suggests that after many hours of cyclic strain, a possible mechanism for cell hypertrophy is the accumulation of thin filament assembly triggered partially by the increased PIP2 level and its binding to CapZ.
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Jieli
authors.initials: J
authors.lastname: Li
authors.forename: Brenda
authors.initials: B
authors.lastname: Russell
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D051347:CapZ Actin Capping Protein / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007700:Kinetics; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013314:Stress, Mechanical; D014162:Transfection; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D051347:CapZ Actin Capping Protein; D004791:Enzyme Inhibitors; D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: CapZ tentacle; actin assembly; cardiac hypertrophy; mechanotransduction; phosphoinositide
references.citation: Annu Rev Physiol. 2003;65:761-89
references.pmid: 12471164
references.citation: Trends Biochem Sci. 2004 Aug;29(8):418-28
references.pmid: 15362226
references.citation: Am J Physiol Heart Circ Physiol. 2005 Oct;289(4):H1488-96
references.pmid: 15923313
references.citation: J Mol Cell Cardiol. 2010 May;48(5):817-23
references.pmid: 20188736
references.citation: J Cell Biol. 2009 Nov 30;187(5):715-31
references.pmid: 19948488
references.citation: Circ Res. 2002 Jun 28;90(12):1299-306
references.pmid: 12089068
references.citation: Biochem J. 2004 Mar 15;378(Pt 3):1067-72
references.pmid: 14670080
references.citation: Cell. 1999 Sep 3;98(5):555-8
references.pmid: 10490095
references.citation: J Cell Biol. 1999 Dec 13;147(6):1287-98
references.pmid: 10601341
references.citation: J Biol Chem. 2007 Feb 23;282(8):5871-9
references.pmid: 17182619
references.citation: J Cell Physiol. 2005 Sep;204(3):934-47
references.pmid: 15828024
references.citation: Theor Biol Med Model. 2006 Aug 16;3:30
references.pmid: 16914033
references.citation: J Biol Chem. 2009 Dec 18;284(51):35278-82
references.pmid: 19808673
references.citation: Hypertension. 2002 Feb;39(2):233-8
references.pmid: 11847190
references.citation: J Cell Biol. 1996 Oct;135(1):169-79
references.pmid: 8858171
references.citation: Am J Physiol Heart Circ Physiol. 2000 May;278(5):H1695-707
references.pmid: 10775151
references.citation: Mol Biol Cell. 2006 Apr;17(4):1946-58
references.pmid: 16436516
references.citation: Circ Res. 1995 Feb;76(2):261-8
references.pmid: 7834837
references.citation: J Biol Chem. 2004 Feb 27;279(9):7840-9
references.pmid: 14681219
references.citation: Nat Cell Biol. 2002 Apr;4(4):E91-6
references.pmid: 11944042
references.citation: PLoS One. 2011;6(8):e23736
references.pmid: 21901132
references.citation: J Biol Chem. 2000 Apr 7;275(14):10168-74
references.pmid: 10744700
references.citation: Am J Physiol Cell Physiol. 2009 May;296(5):C1034-9
references.pmid: 19295171
references.citation: J Cell Biol. 1992 Feb;116(4):923-31
references.pmid: 1370838
references.citation: J Cell Sci. 2005 Apr 1;118(Pt 7):1461-72
references.pmid: 15769850
references.citation: J Cell Biol. 1994 Oct;127(2):453-65
references.pmid: 7929588
references.citation: FEBS Lett. 2007 Sep 4;581(22):4241-7
references.pmid: 17698065
references.citation: Curr Biol. 2003 Sep 2;13(17):1531-7
references.pmid: 12956956
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H259-69
references.pmid: 16963613
references.citation: Biochim Biophys Acta. 2003 Feb 17;1593(2-3):121-9
references.pmid: 12581856
references.citation: Cell. 2002 Sep 20;110(6):673-87
references.pmid: 12297042
references.citation: Am J Physiol Cell Physiol. 2003 Jul;285(1):C171-82
references.pmid: 12672651
references.citation: PLoS One. 2010 Jul 12;5(7):e11470
references.pmid: 20635003
references.citation: FEBS Lett. 1996 Jan 15;378(3):258-62
references.pmid: 8557113
references.citation: J Mol Cell Cardiol. 2006 Sep;41(3):537-43
references.pmid: 16870209
references.citation: EMBO J. 2003 Apr 1;22(7):1529-38
references.pmid: 12660160
references.citation: Cell. 1998 Apr 17;93(2):215-28
references.pmid: 9568714
references.citation: Cell Calcium. 2001 Feb;29(2):73-83
references.pmid: 11162845
references.citation: Pflugers Arch. 2007 Oct;455(1):5-18
references.pmid: 17520274
references.citation: J Biol Chem. 2005 Apr 15;280(15):15479-82
references.pmid: 15710624
references.citation: Nature. 1996 Jun 6;381(6582):531-5
references.pmid: 8632828
references.citation: J Appl Physiol (1985). 2013 Jun;114(11):1603-9
references.pmid: 23493359
references.citation: J Cell Biol. 1995 Jan;128(1-2):61-70
references.pmid: 7822423
references.citation: Int Rev Cell Mol Biol. 2008;267:183-206
references.pmid: 18544499
references.citation: Ann Intern Med. 1994 Sep 1;121(5):363-71
references.pmid: 8042826
references.citation: Eur J Biochem. 1999 Jul;263(1):85-92
references.pmid: 10429191