title: Getting the skinny on thick filament regulation in cardiac muscle biology and disease.
abstract: Thin (actin) filament accessory proteins are thought to be the regulatory force for muscle contraction in cardiac muscle; however, compelling new evidence suggests that thick (myosin) filament regulatory proteins are emerging as having independent and important roles in regulating cardiac muscle contraction. Key to these new findings is a growing body of evidence that point to an influential and, more recently, direct role for ventricular myosin light chain-2 (MLC2v) phosphorylation in regulating cardiac muscle contraction, function, and disease. This includes the discovery and characterization of a cardiac-specific myosin light chain kinase capable of phosphorylating MLC2v as well as a myosin phosphatase that dephosphorylates MLC2v in the heart, which provides added mechanistic insights on MLC2v regulation within cardiac muscle. Here, we review evidence for an emerging and critical role for MLC2v phosphorylation in regulating cardiac myosin cycling kinetics, function, and disease, based on recent studies performed in genetic mouse models and humans. We further provide new perspectives on future avenues for targeting these pathways as therapies in alleviating cardiac disease.
authors: Department of Medicine (Cardiology Division), University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: fasheikh@ucsd.edu.
authors: Farah
authors: F
authors: Sheikh
authors: Department of Medicine (Cardiology Division), University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors: Robert C
authors: RC
authors: Lyon
authors: Department of Medicine (Cardiology Division), University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: juchen@ucsd.edu.
authors: Ju
authors: J
authors: Chen
mesh_terms: D000818:Animals; D024722:Cardiac Myosins / Q000235:genetics / Q000378:metabolism*; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D009119:Muscle Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D018994:Myosin Light Chains; D009219:Myosin-Light-Chain Kinase; D043263:Myosin-Light-Chain Phosphatase; D024722:Cardiac Myosins
references: Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):318-23
references: 23251030
references: Cardiovasc Res. 2009 Apr 1;82(1):84-92
references: 19150977
references: Circ Res. 2008 Mar 14;102(5):571-80
references: 18202317
references: J Biol Chem. 1998 Jan 9;273(2):1252-6
references: 9422794
references: Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1490-4
references: 8108436
references: J Cell Mol Med. 2012 Apr;16(4):911-9
references: 21696541
references: Nature. 1969 Sep 27;223(5213):1362-4
references: 5809510
references: Annu Rev Cell Biol. 1987;3:379-421
references: 3318880
references: Biochem J. 1975 Oct;151(1):99-107
references: 1212218
references: Circ J. 2010 Jan;74(1):120-8
references: 19966500
references: J Biol Chem. 2011 Apr 8;286(14):12650-8
references: 21297165
references: Science. 1993 Jul 2;261(5117):50-8
references: 8316857
references: J Physiol. 1998 Oct 15;512 ( Pt 2):345-50
references: 9763625
references: Biochem J. 2012 Feb 15;442(1):95-103
references: 22091967
references: J Mol Biol. 2006 Jun 9;359(3):509-25
references: 16678204
references: J Biol Chem. 1986 Jan 5;261(1):36-9
references: 3079756
references: Cardiovasc Res. 2008 Aug 1;79(3):481-91
references: 18411228
references: Nat Genet. 1996 May;13(1):63-9
references: 8673105
references: J Mol Cell Cardiol. 2006 Aug;41(2):330-9
references: 16806259
references: Cardiovasc Res. 2003 Jan;57(1):37-47
references: 12504812
references: J Clin Invest. 2007 Oct;117(10):2812-24
references: 17885681
references: Basic Res Cardiol. 1992;87 Suppl 1:129-41
references: 1386730
references: Cell Mol Life Sci. 2013 Apr;70(7):1221-39
references: 22955375
references: Biophys J. 1996 Aug;71(2):898-907
references: 8842229
references: J Biol Chem. 2001 Mar 9;276(10):7086-92
references: 11102452
references: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17519-24
references: 16299103
references: J Biol Chem. 1979 Dec 10;254(23):12136-44
references: 500701
references: J Gen Physiol. 1989 May;93(5):855-83
references: 2661721
references: J Physiol. 2010 Mar 15;588(Pt 6):981-93
references: 20123786
references: J Gen Physiol. 2006 Sep;128(3):261-72
references: 16908724
references: Cell. 2001 Nov 30;107(5):631-41
references: 11733062
references: Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):114-9
references: 21149681
references: Cardiovasc Res. 2003 Feb;57(2):505-14
references: 12566123
references: Circ Res. 2008 Mar 14;102(5):516-8
references: 18340016
references: J Biol Chem. 2008 Jul 11;283(28):19748-56
references: 18474588
references: Circulation. 2001 Sep 4;104(10):1140-6
references: 11535570
references: J Biol Chem. 2013 May 10;288(19):13446-54
references: 23530050
references: Am J Physiol. 1993 May;264(5 Pt 1):C1085-95
references: 8388631
references: J Biol Chem. 1999 Jul 23;274(30):21085-94
references: 10409661
references: Mol Cell Proteomics. 2010 Sep;9(9):1804-18
references: 20445002
references: Am J Physiol Heart Circ Physiol. 2004 Dec;287(6):H2712-8
references: 15331360
references: J Biol Chem. 2011 Mar 25;286(12):9941-7
references: 21257758
references: Am J Physiol Regul Integr Comp Physiol. 2009 Aug;297(2):R265-74
references: 19458282
references: Cell Signal. 2006 Sep;18(9):1408-16
references: 16431080
references: J Biol Chem. 2010 Feb 19;285(8):5122-6
references: 20038585
references: Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17403-8
references: 20855589
references: Circulation. 2012 Nov 27;126(22):2575-88
references: 23095280
references: J Clin Invest. 2012 Apr;122(4):1209-21
references: 22426213
references: J Biol Chem. 2010 Dec 24;285(52):40819-29
references: 20943660
references: J Biol Chem. 2009 Feb 20;284(8):5097-106
references: 19106098
references: Arch Biochem Biophys. 2006 Dec 15;456(2):216-23
references: 16949549