MYL2

MYL2
Identifiers
Aliases MYL2, CMH10, MLC2, MLC-2s/v, myosin light chain 2
External IDs MGI: 97272 HomoloGene: 55462 GeneCards: MYL2
Genetically Related Diseases
coronary artery disease[1]
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez

4633

17906

Ensembl

ENSG00000111245

ENSMUSG00000013936

UniProt

P10916

P51667

RefSeq (mRNA)

NM_000432

NM_010861

RefSeq (protein)

NP_000423.2

NP_034991.3

Location (UCSC) Chr 12: 110.91 – 110.92 Mb Chr 5: 122.1 – 122.11 Mb
PubMed search [2] [3]
Wikidata
View/Edit HumanView/Edit Mouse

Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the MYL2 gene.[4][5] This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7).[6]

Ventricular myosin light chain-2 (MLC-2v) refers to the ventricular cardiac muscle form of myosin light chain 2 (Myl2). MLC-2v is a 19-KDa protein composed of 166 amino acids, that belongs to the EF-hand Ca2+ binding superfamily.[7] MLC-2v interacts with the neck/tail region of the muscle thick filament protein myosin to regulate myosin motility and function.[8]

Structure

Cardiac, ventricular RLC is an 18.8 kDa protein composed of 166 amino acids.[9][10] RLC and the second ventricular light chain, essential light chain (ELC, MYL3), are non-covalently bound to IQXXXRGXXXR motifs in the 9 nm S1-S2 lever arm of the myosin head,[11] both alpha (MYH6) and beta (MYH7) isoforms. Both light chains are members of the EF-hand superfamily of proteins, which possess two helix-loop-helix motifs in two globular domains connected by an alpha-helical linker.

Function

The N-terminal EF-hand domain of RLC binds calcium/magnesium at activating concentrations,[12] however the dissociation rate is too slow to modulate cardiac contractility on a beat-by-beat basis.[13] Perturbing the calcium binding region of RLC through site-directed mutagenesis (D47A) decreased tension and stiffness in isolated, skinned skeletal muscle fibers,[14] suggesting that the conformational change induced by calcium binding to RLC is functionally important.[15]

Another mode of RLC modulation lies in its ability to be modified by phosphorylation and deamidation in the N-terminal region, resulting in significant charge alterations of the protein. RLC is phosphorylated by a cardiac-specific myosin light chain kinase (MYLK3), which was recently cloned.[16] Studies have supported a role for myosin phosphatase targeting subunit 2 (MYPT2,PPP1R12B) in the dephosphorylation of RLC.[17] Human RLC has an Asparagine at position 14 (Threonine in mouse) and a Serine at position 15 (same in mouse). Endogenous RLC exists as a mixture of unmodified (typically ~50%), singly-modified (either N14 deamidation or S15 phosphorylation) and doubly modified (N14 deamidation and S15 phosphorylation) protein.[6] Both deamidation and phosphorylation contribute negative charge to the N-terminal region of RLC, undoubtedly altering its interaction with the C-terminal myosin alpha helical domain. Functional studies have supported a role for RLC phosphorylation in modulating cardiac myosin crossbridge kinetics. It is well established that RLC phosphorylation enhances myofilament sensitivity to calcium in isometrically-contracting, skinned cardiac fibers.[18][19] It was also demonstrated that a lack of RLC phosphorylation decreases tension cost (isometric force/ATPase rate at a given pCa), suggesting that RLC phosphorylation augments cycling kinetics of myosin.[20] It has been proposed that RLC phosphorylation promotes a "swing-out" of myosin heads, facilitating weak-to-strong crossbridge binding to actin per unit calcium.[21] Additional insights regarding RLC phosphorylation in beating hearts have come from in vivo studies. Adult mice expressing a non-phosphorylatable cardiac RLC (TG-RLC(P-)) exhibited significant decreases in load-dependent[22] and load-independent measures of contractility.[20] In TG-RLC(P-), the time for the heart to reach peak elastance during ejection was elongated, ejection capacity was decreased and the inotropic response to dobutamine was blunted.[20] It is also clear that ablation of RLC phosphorylation in vivo induces alterations in the phosphorylation of other sarcomeric proteins, namely cardiac myosin binding protein C and cardiac troponin I. Moreover, RLC phosphorylation, specifically, appears to be necessary for a normal inotropic response to dobutamine.[20] In agreement with these findings, a second in vivo model, cardiac myosin light chain kinase (MYLK3) knockout (cMLCK neo/neo), showed depressed fractional shortening, progressing to left ventricular hypertrophy by 4–5 months of age.[23] Taken together, these studies clearly demonstrate that RLC phosphorylation regulates cardiac dynamics in beating hearts, and is critical for eliciting a normal sympathetic response.

Expression patterns during cardiac development

MLC-2v plays an essential role in early embryonic cardiac development and function.[24] and represents one of the earliest markers of ventricular specification.[25] During early development (E7.5-8.0), MLC-2v is expressed within the cardiac crescent. The expression pattern of MLC-2v becomes restricted to the ventricular segment of the linear heart tube at E8.0 and remains restricted within the ventricle into adulthood.[25][26]

Phosphorylation sites and regulators

Recent studies have highlighted a critical role for MLC2v phosphorylation in cardiac torsion, function and disease.[27] In cardiac muscle, the critical phosphorylation sites have been identified as Ser14/Ser15 in the mouse heart and Ser15 in the human heart.[28] The major kinase responsible for MLC-2v phosphorylation has been identified as cardiac myosin light chain kinase (MLCK), encoded for by Mylk3.[28][29] Loss of cardiac MLCK in mice results in loss of cardiac MLC-2v phosphorylation and cardiac abnormalities.[23][30]

Clinical significance

Mutations in MYL2 have been associated with familial hypertrophic cardiomyopathy (FHC). Ten FHC mutations have been identified in RLC: E22K, A13T, N47K, P95A, F18L, R58Q, IVS6-1G>C, L103E, IVS5-2A>G, D166V. The first three-E22K, A13T and N47K-have been associated with an unusual mid-ventricular chamber obstruction type of hypertrophy.[31][32] Three mutations-R58Q, D166V and IVS5-2-are associated with more malignant outcomes, manifesting with sudden cardiac death or at earlier ages.[33][34][35][36] Functional studies demonstrate that FHC mutations in RLC affect its ability to both be phosphorylated and to bind calcium/magnesium.[37]

Effects on cardiac muscle contraction

MLC-2v plays an important role in cross-bridge cycling kinetics and cardiac muscle contraction.[38] MLC-2v phosphorylation at Ser14 and Ser15 increases myosin lever arm stiffness and promotes myosin head diffusion, which altogether slow down myosin kinetics and prolong the duty cycle as a means to fine-tune myofilament Ca2+ sensitivity to force.[38]

Effects on adult cardiac torsion, function and disease

A gradient in the levels of both MLC2v phosphorylation and its kinase, cardiac MLCK, has been shown to exist across the human heart from endocardium (low phosphorylation) to epicardium (high phosphorylation).[39] The existence of this gradient has been proposed to impact cardiac torsion due to the relative spatial orientation of endocardial versus epicardial myofibers.[39] In support of this, recent studies have shown that MLC-2v phosphorylation is critical in regulating left ventricular torsion.[30][38] Variations in myosin cycling kinetics and contractile properties as a result of differential MLC-2v phosphorylation (Ser14/15) influence both epicardial and endocardial myofiber tension development and recovery to control cardiac torsion and myofiber strain mechanics.<ref name = "Warren_2012"/[38]

A number of human studies have implicated loss of MLC-2v phosphorylation in the pathogenesis of human dilated cardiomyopathy and heart failure.[28][40][41][42][43] MLC-2v dephosphorylation has also been reported in human patients carrying a rare form of familial hypertrophic cardiomyopathy (FHC) based on specific MLC-2v and MLCK mutations.[15][39][44]

Animal studies

MLC-2v plays a key role in the regulation of cardiac muscle contraction, through its interactions with myosin.[27] Loss of MLC-2v in mice is associated with ultrastructural defects in sarcomere assembly and results in dilated cardiomyopathy and heart failure with reduced ejection fraction, leading to embryonic lethality at E12.5.[24] More recently, a mutation in zebrafish tell tale heart (telm225) that encodes MLC-2, demonstrated that cardiac MLC-2 is required for thick filament stabilization and contractility in the embryonic zebrafish heart.[45]

The role of Myl2 mutations in pathogenesis has been determined through the generation of a number of mouse models.[38][46][47] Transgenic mice overexpressing the human MLC-2v R58Q mutation, which is associated with FHC has been shown to lead to a reduction in MLC-2v phosphorylation in hearts.[46] These mice exhibited features of FHC, including diastolic dysfunction that progressed with age.[46] Similarly, cardiac overexpression of another FHC-associated MLC-2v mutation (D166V) results in loss of MLC-2v phosphorylation in mouse hearts.[47] In addition to these findings, MLC-2v dephosphorylation in mice results in cardiac dilatation and dysfunction associated with features reminiscent of dilated cardiomyopathy, leading to heart failure and premature death.[17][30][38] Altogether these studies highlight a role for MLC-2v phosphorylation in adult heart function. These studies also suggest that torsion defects might be an early manifestation of dilated cardiomyopathy consequent to loss of MLC-2v phosphorylation.[38] MLC-2v also plays an important role in cardiac stress associated with hypertrophy.[30][38] In a novel MLC2v Ser14Ala/Ser15Ala knockin mouse model, complete loss of MLC2v (Ser14/Ser15) phosphorylation led to a worsened and differential (eccentric as opposed to concentric) response to pressure overload-induced hypertrophy.[38] In addition, mice lacking cardiac MLCK display heart failure and experience premature death in response to both pressure overload and swimming induced hypertrophy.[30] Consistent with these findings, a cardiac-specific transgenic mouse model overexpressing cardiac MLCK attenuated the response to cardiac hypertrophy induced by pressure overload.[30] Furthermore, in a cardiac-specific transgenic mouse model overexpressing skeletal myosin light chain kinase, the response to cardiac hypertrophy induced by treadmill exercise or isoproterenol was also attenuated.[48] These studies further highlight the therapeutic potential of increasing MLC-2v phosphorylation in settings of cardiac pathological stress.

References

  1. ↑ "Diseases that are genetically associated with MYL2 view/edit references on wikidata".
  2. ↑ "Human PubMed Reference:".
  3. ↑ "Mouse PubMed Reference:".
  4. ↑ Macera MJ, Szabo P, Wadgaonkar R, Siddiqui MA, Verma RS (Jul 1992). "Localization of the gene coding for ventricular myosin regulatory light chain (MYL2) to human chromosome 12q23-q24.3". Genomics. 13 (3): 829–31. doi:10.1016/0888-7543(92)90161-K. PMID 1386340.
  5. ↑ "Entrez Gene: MYL2 myosin, light chain 2, regulatory, cardiac, slow".
  6. 1 2 Scruggs SB, Solaro RJ (Jun 2011). "The significance of regulatory light chain phosphorylation in cardiac physiology". Archives of Biochemistry and Biophysics. 510 (2): 129–34. doi:10.1016/j.abb.2011.02.013. PMC 3114105Freely accessible. PMID 21345328.
  7. ↑ Grabarek Z (Jun 2006). "Structural basis for diversity of the EF-hand calcium-binding proteins". Journal of Molecular Biology. 359 (3): 509–25. doi:10.1016/j.jmb.2006.03.066. PMID 16678204.
  8. ↑ Rayment I, Holden HM, Whittaker M, Yohn CB, Lorenz M, Holmes KC, Milligan RA (Jul 1993). "Structure of the actin-myosin complex and its implications for muscle contraction". Science. 261 (5117): 58–65. doi:10.1126/science.8316858. PMID 8316858.
  9. ↑ "MYL2 protein". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  10. ↑ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475Freely accessible. PMID 23965338.
  11. ↑ Rayment I, Rypniewski WR, Schmidt-Bäse K, Smith R, Tomchick DR, Benning MM, Winkelmann DA, Wesenberg G, Holden HM (1993). "Three-dimensional structure of myosin subfragment-1: a molecular motor". Science. 261 (5117): 50–8. doi:10.1126/science.8316857. PMID 8316857.
  12. ↑ Morimoto K, Harrington WF (Sep 1974). "Evidence for structural changes in vertebrate thick filaments induced by calcium". Journal of Molecular Biology. 88 (3): 693–709. doi:10.1016/0022-2836(74)90417-3. PMID 4449125.
  13. ↑ Bagshaw CR (1977). "On the location of the divalent metal binding sites and the light chain subunits of vertebrate myosin". Biochemistry. 16 (1): 59–67. doi:10.1021/bi00620a010. PMID 188447.
  14. ↑ Diffee GM, Patel JR, Reinach FC, Greaser ML, Moss RL (Jul 1996). "Altered kinetics of contraction in skeletal muscle fibers containing a mutant myosin regulatory light chain with reduced divalent cation binding". Biophysical Journal. 71 (1): 341–50. doi:10.1016/S0006-3495(96)79231-7. PMC 1233485Freely accessible. PMID 8804617.
  15. 1 2 Szczesna D, Ghosh D, Li Q, Gomes AV, Guzman G, Arana C, Zhi G, Stull JT, Potter JD (Mar 2001). "Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation". The Journal of Biological Chemistry. 276 (10): 7086–92. doi:10.1074/jbc.M009823200. PMID 11102452.
  16. ↑ Chan JY, Takeda M, Briggs LE, Graham ML, Lu JT, Horikoshi N, Weinberg EO, Aoki H, Sato N, Chien KR, Kasahara H (Mar 2008). "Identification of cardiac-specific myosin light chain kinase". Circulation Research. 102 (5): 571–80. doi:10.1161/CIRCRESAHA.107.161687. PMC 2504503Freely accessible. PMID 18202317.
  17. 1 2 Mizutani H, Okamoto R, Moriki N, Konishi K, Taniguchi M, Fujita S, Dohi K, Onishi K, Suzuki N, Satoh S, Makino N, Itoh T, Hartshorne DJ, Ito M (Jan 2010). "Overexpression of myosin phosphatase reduces Ca(2+) sensitivity of contraction and impairs cardiac function". Circulation Journal. 74 (1): 120–8. doi:10.1253/circj.cj-09-0462. PMID 19966500.
  18. ↑ Morano I, Hofmann F, Zimmer M, Rüegg JC (Sep 1985). "The influence of P-light chain phosphorylation by myosin light chain kinase on the calcium sensitivity of chemically skinned heart fibres". FEBS Letters. 189 (2): 221–4. doi:10.1016/0014-5793(85)81027-9. PMID 3840099.
  19. ↑ Olsson MC, Patel JR, Fitzsimons DP, Walker JW, Moss RL (Dec 2004). "Basal myosin light chain phosphorylation is a determinant of Ca2+ sensitivity of force and activation dependence of the kinetics of myocardial force development". American Journal of Physiology. Heart and Circulatory Physiology. 287 (6): H2712–8. doi:10.1152/ajpheart.01067.2003. PMID 15331360.
  20. 1 2 3 4 Scruggs SB, Hinken AC, Thawornkaiwong A, Robbins J, Walker LA, de Tombe PP, Geenen DL, Buttrick PM, Solaro RJ (Feb 2009). "Ablation of ventricular myosin regulatory light chain phosphorylation in mice causes cardiac dysfunction in situ and affects neighboring myofilament protein phosphorylation". The Journal of Biological Chemistry. 284 (8): 5097–106. doi:10.1074/jbc.M807414200. PMC 2643522Freely accessible. PMID 19106098.
  21. ↑ Metzger JM, Greaser ML, Moss RL (May 1989). "Variations in cross-bridge attachment rate and tension with phosphorylation of myosin in mammalian skinned skeletal muscle fibers. Implications for twitch potentiation in intact muscle". The Journal of General Physiology. 93 (5): 855–83. doi:10.1085/jgp.93.5.855. PMC 2216237Freely accessible. PMID 2661721.
  22. ↑ Sanbe A, Fewell JG, Gulick J, Osinska H, Lorenz J, Hall DG, Murray LA, Kimball TR, Witt SA, Robbins J (Jul 1999). "Abnormal cardiac structure and function in mice expressing nonphosphorylatable cardiac regulatory myosin light chain 2". The Journal of Biological Chemistry. 274 (30): 21085–94. doi:10.1074/jbc.274.30.21085. PMID 10409661.
  23. 1 2 Ding P, Huang J, Battiprolu PK, Hill JA, Kamm KE, Stull JT (Dec 2010). "Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo". The Journal of Biological Chemistry. 285 (52): 40819–29. doi:10.1074/jbc.M110.160499. PMC 3003383Freely accessible. PMID 20943660.
  24. 1 2 Chen J, Kubalak SW, Minamisawa S, Price RL, Becker KD, Hickey R, Ross J, Chien KR (Jan 1998). "Selective requirement of myosin light chain 2v in embryonic heart function". The Journal of Biological Chemistry. 273 (2): 1252–6. doi:10.1074/jbc.273.2.1252. PMID 9422794.
  25. 1 2 O'Brien TX, Lee KJ, Chien KR (Jun 1993). "Positional specification of ventricular myosin light chain 2 expression in the primitive murine heart tube". Proceedings of the National Academy of Sciences of the United States of America. 90 (11): 5157–61. doi:10.1073/pnas.90.11.5157. PMID 8506363.
  26. ↑ Ross RS, Navankasattusas S, Harvey RP, Chien KR (Jun 1996). "An HF-1a/HF-1b/MEF-2 combinatorial element confers cardiac ventricular specificity and established an anterior-posterior gradient of expression". Development. 122 (6): 1799–809. PMID 8674419.
  27. 1 2 Sheikh F, Lyon RC, Chen J (May 2014). "Getting the skinny on thick filament regulation in cardiac muscle biology and disease". Trends in Cardiovascular Medicine. 24 (4): 133–41. doi:10.1016/j.tcm.2013.07.004. PMID 23968570.
  28. 1 2 3 Scruggs SB, Reisdorph R, Armstrong ML, Warren CM, Reisdorph N, Solaro RJ, Buttrick PM (Sep 2010). "A novel, in-solution separation of endogenous cardiac sarcomeric proteins and identification of distinct charged variants of regulatory light chain". Molecular & Cellular Proteomics. 9 (9): 1804–18. doi:10.1074/mcp.M110.000075. PMID 20445002.
  29. ↑ Seguchi O, Takashima S, Yamazaki S, Asakura M, Asano Y, Shintani Y, Wakeno M, Minamino T, Kondo H, Furukawa H, Nakamaru K, Naito A, Takahashi T, Ohtsuka T, Kawakami K, Isomura T, Kitamura S, Tomoike H, Mochizuki N, Kitakaze M (Oct 2007). "A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart". The Journal of Clinical Investigation. 117 (10): 2812–24. doi:10.1172/JCI30804. PMC 1978424Freely accessible. PMID 17885681.
  30. 1 2 3 4 5 6 Warren SA, Briggs LE, Zeng H, Chuang J, Chang EI, Terada R, Li M, Swanson MS, Lecker SH, Willis MS, Spinale FG, Maupin-Furlowe J, McMullen JR, Moss RL, Kasahara H (Nov 2012). "Myosin light chain phosphorylation is critical for adaptation to cardiac stress". Circulation. 126 (22): 2575–88. doi:10.1161/CIRCULATIONAHA.112.116202. PMID 23095280.
  31. ↑ Poetter K, Jiang H, Hassanzadeh S, Master SR, Chang A, Dalakas MC, Rayment I, Sellers JR, Fananapazir L, Epstein ND (May 1996). "Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle". Nature Genetics. 13 (1): 63–9. doi:10.1038/ng0596-63. PMID 8673105.
  32. ↑ Andersen PS, Havndrup O, Bundgaard H, Moolman-Smook JC, Larsen LA, Mogensen J, Brink PA, Børglum AD, Corfield VA, Kjeldsen K, Vuust J, Christiansen M (Dec 2001). "Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations". Journal of Medical Genetics. 38 (12): E43. doi:10.1136/jmg.38.12.e43. PMC 1734772Freely accessible. PMID 11748309.
  33. ↑ Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M (May 2003). "Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy". Circulation. 107 (17): 2227–32. doi:10.1161/01.CIR.0000066323.15244.54. PMID 12707239.
  34. ↑ Flavigny J, Richard P, Isnard R, Carrier L, Charron P, Bonne G, Forissier JF, Desnos M, Dubourg O, Komajda M, Schwartz K, Hainque B (Mar 1998). "Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy". Journal of Molecular Medicine. 76 (3-4): 208–14. doi:10.1007/s001090050210. PMID 9535554.
  35. ↑ Kabaeva ZT, Perrot A, Wolter B, Dietz R, Cardim N, Correia JM, Schulte HD, Aldashev AA, Mirrakhimov MM, Osterziel KJ (Nov 2002). "Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy". European Journal of Human Genetics. 10 (11): 741–8. doi:10.1038/sj.ejhg.5200872. PMID 12404107.
  36. ↑ Mörner S, Richard P, Kazzam E, Hellman U, Hainque B, Schwartz K, Waldenström A (Jul 2003). "Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden". Journal of Molecular and Cellular Cardiology. 35 (7): 841–9. doi:10.1016/s0022-2828(03)00146-9. PMID 12818575.
  37. ↑ Harris SP, Lyons RG, Bezold KL (Mar 2011). "In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament". Circulation Research. 108 (6): 751–64. doi:10.1161/CIRCRESAHA.110.231670. PMC 3076008Freely accessible. PMID 21415409.
  38. 1 2 3 4 5 6 7 8 9 Sheikh F, Ouyang K, Campbell SG, Lyon RC, Chuang J, Fitzsimons D, Tangney J, Hidalgo CG, Chung CS, Cheng H, Dalton ND, Gu Y, Kasahara H, Ghassemian M, Omens JH, Peterson KL, Granzier HL, Moss RL, McCulloch AD, Chen J (Apr 2012). "Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease". The Journal of Clinical Investigation. 122 (4): 1209–21. doi:10.1172/JCI61134. PMC 3314469Freely accessible. PMID 22426213.
  39. 1 2 3 Davis JS, Hassanzadeh S, Winitsky S, Lin H, Satorius C, Vemuri R, Aletras AH, Wen H, Epstein ND (Nov 2001). "The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation". Cell. 107 (5): 631–41. doi:10.1016/s0092-8674(01)00586-4. PMID 11733062.
  40. ↑ Morano I (1992). "Effects of different expression and posttranslational modifications of myosin light chains on contractility of skinned human cardiac fibers". Basic Research in Cardiology. 87 Suppl 1: 129–41. doi:10.1007/978-3-642-72474-9_11. PMID 1386730.
  41. ↑ van Der Velden J, Klein LJ, Zaremba R, Boontje NM, Huybregts MA, Stooker W, Eijsman L, de Jong JW, Visser CA, Visser FC, Stienen GJ (Sep 2001). "Effects of calcium, inorganic phosphate, and pH on isometric force in single skinned cardiomyocytes from donor and failing human hearts". Circulation. 104 (10): 1140–6. doi:10.1161/hc3501.095485. PMID 11535570.
  42. ↑ van der Velden J, Papp Z, Zaremba R, Boontje NM, de Jong JW, Owen VJ, Burton PB, Goldmann P, Jaquet K, Stienen GJ (Jan 2003). "Increased Ca2+-sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins". Cardiovascular Research. 57 (1): 37–47. doi:10.1016/s0008-6363(02)00606-5. PMID 12504812.
  43. ↑ van der Velden J, Papp Z, Boontje NM, Zaremba R, de Jong JW, Janssen PM, Hasenfuss G, Stienen GJ (Feb 2003). "The effect of myosin light chain 2 dephosphorylation on Ca2+ -sensitivity of force is enhanced in failing human hearts". Cardiovascular Research. 57 (2): 505–14. doi:10.1016/s0008-6363(02)00662-4. PMID 12566123.
  44. ↑ Jacques AM, Briceno N, Messer AE, Gallon CE, Jalilzadeh S, Garcia E, Kikonda-Kanda G, Goddard J, Harding SE, Watkins H, Esteban MT, Tsang VT, McKenna WJ, Marston SB (Aug 2008). "The molecular phenotype of human cardiac myosin associated with hypertrophic obstructive cardiomyopathy". Cardiovascular Research. 79 (3): 481–91. doi:10.1093/cvr/cvn094. PMID 18411228.
  45. ↑ Rottbauer W, Wessels G, Dahme T, Just S, Trano N, Hassel D, Burns CG, Katus HA, Fishman MC (Aug 2006). "Cardiac myosin light chain-2: a novel essential component of thick-myofilament assembly and contractility of the heart". Circulation Research. 99 (3): 323–31. doi:10.1161/01.RES.0000234807.16034.fe. PMID 16809551.
  46. 1 2 3 Abraham TP, Jones M, Kazmierczak K, Liang HY, Pinheiro AC, Wagg CS, Lopaschuk GD, Szczesna-Cordary D (Apr 2009). "Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice". Cardiovascular Research. 82 (1): 84–92. doi:10.1093/cvr/cvp016. PMID 19150977.
  47. 1 2 Muthu P, Kazmierczak K, Jones M, Szczesna-Cordary D (Apr 2012). "The effect of myosin RLC phosphorylation in normal and cardiomyopathic mouse hearts". Journal of Cellular and Molecular Medicine. 16 (4): 911–9. doi:10.1111/j.1582-4934.2011.01371.x. PMID 21696541.
  48. ↑ Huang J, Shelton JM, Richardson JA, Kamm KE, Stull JT (Jul 2008). "Myosin regulatory light chain phosphorylation attenuates cardiac hypertrophy". The Journal of Biological Chemistry. 283 (28): 19748–56. doi:10.1074/jbc.M802605200. PMID 18474588.

Further reading

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