Home LiteratureArticle Details
PMID: 17442337 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase.

Journal of molecular and cellular cardiology ·Vol. 42 ·No. 5 ·2007-05-00 ·Pages 903-11

Bhupathy P, Babu GJ, Periasamy M

Abstract

The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a critical role in maintaining the intracellular calcium homeostasis during cardiac contraction and relaxation. It has been well documented over the years that altered expression and activity of SERCA2a can lead to systolic and diastolic dysfunction. The activity of SERCA2a is regulated by two structurally similar proteins, phospholamban (PLB) and sarcolipin (SLN). Although, the relevance of PLB has been extensively studied over the years, the role SLN in cardiac physiology is an emerging field of study. This review focuses on the advances in the understanding of the regulation of SERCA2a by SLN and PLB. In particular, it highlights the similarities and differences between the two proteins and their roles in cardiac patho-physiology.

MeSH Terms
Animals Calcium-Binding Proteins/chemistry,metabolism Heart Humans Muscle Proteins/chemistry,metabolism Myocardium/enzymology,metabolism Proteolipids/chemistry,metabolism Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism
Chemicals
Calcium-Binding Proteins Muscle Proteins Proteolipids phospholamban sarcolipin Sarcoplasmic Reticulum Calcium-Transporting ATPases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Bhupathy Poornima
Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA.
Babu Gopal J
Periasamy Muthu
References (81)
81 references, click to expand
  1. Animal models of human cardiovascular disease, heart failure and hypertrophy.
    Cardiovasc Res. 1998 Jul;39(1):60-76 PMID: 9764190
  2. Decreased expression of phospholamban is not associated with lower beta-adrenergic activation in rat atria.
    Mol Cell Biochem. 2001 Jul;223(1-2):109-15 PMID: 11681711
  3. Patients with end-stage congestive heart failure treated with beta-adrenergic receptor antagonists have improved ventricular myocyte calcium regulatory protein abundance.
    Circulation. 2001 Aug 28;104(9):1012-8 PMID: 11524394
  4. Age-related alterations in the phosphorylation of sarcoplasmic reticulum and myofibrillar proteins and diminished contractile response to isoproterenol in intact rat ventricle.
    Circ Res. 1993 Jan;72(1):102-11 PMID: 8380258
  5. Atrial chamber-specific expression of sarcolipin is regulated during development and hypertrophic remodeling.
    J Biol Chem. 2003 Mar 14;278(11):9570-5 PMID: 12645548
  6. Alterations of calcium-regulatory proteins in heart failure.
    Cardiovasc Res. 1998 Feb;37(2):279-89 PMID: 9614485
  7. The vmax of the Ca2+-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) is not altered by Ca2+/calmodulin-dependent phosphorylation or by interaction with phospholamban.
    J Biol Chem. 1996 Jun 14;271(24):14206-13 PMID: 8662932
  8. SERCA pump level is a critical determinant of Ca(2+)homeostasis and cardiac contractility.
    J Mol Cell Cardiol. 2001 Jun;33(6):1053-63 PMID: 11444913
  9. Identification of the major protein phosphatases in mammalian cardiac muscle which dephosphorylate phospholamban.
    Eur J Biochem. 1991 Mar 28;196(3):725-34 PMID: 1849481
  10. Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium.
    Circ Res. 1994 Sep;75(3):434-42 PMID: 8062417
  11. Calcium cycling in congestive heart failure.
    J Mol Cell Cardiol. 2002 Aug;34(8):951-69 PMID: 12234765
  12. Phospholamban, activator of the cardiac sarcoplasmic reticulum calcium pump. Physicochemical properties and diagonal purification.
    Biochemistry. 1980 Jul 8;19(14):3368-73 PMID: 6105875
  13. Sarcolipin and phospholamban mRNA and protein expression in cardiac and skeletal muscle of different species.
    Biochem J. 2005 Jul 1;389(Pt 1):151-9 PMID: 15801907
  14. A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy.
    Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1388-93 PMID: 16432188
  15. Sarcolipin retention in the endoplasmic reticulum depends on its C-terminal RSYQY sequence and its interaction with sarco(endo)plasmic Ca(2+)-ATPases.
    Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16807-12 PMID: 15556994
  16. Defining the intramembrane binding mechanism of sarcolipin to calcium ATPase using solution NMR spectroscopy.
    J Mol Biol. 2006 Apr 28;358(2):420-9 PMID: 16519897
  17. Decreased sarcoplasmic reticulum calcium content is responsible for defective excitation-contraction coupling in canine heart failure.
    Circulation. 2001 Mar 20;103(11):1577-84 PMID: 11257088
  18. A leucine zipper stabilizes the pentameric membrane domain of phospholamban and forms a coiled-coil pore structure.
    J Biol Chem. 1996 Mar 8;271(10):5941-6 PMID: 8621468
  19. The nature of the modulation of Ca2+ transport as studied by reconstitution of cardiac sarcoplasmic reticulum.
    J Biol Chem. 1986 Feb 5;261(4):1794-800 PMID: 2935532
  20. Regulation of sarcoplasmic reticulum gene expression during cardiac and skeletal muscle development.
    Am J Physiol. 1992 Mar;262(3 Pt 1):C614-20 PMID: 1372478
  21. Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block.
    Cell. 2004 Apr 30;117(3):373-86 PMID: 15109497
  22. Phosphorylation of phospholamban in the intact heart. A study on the physiological role of the Ca(2+)-calmodulin-dependent protein kinase system.
    J Mol Cell Cardiol. 1992 Apr;24(4):387-96 PMID: 1320129
  23. The relative phospholamban and SERCA2 ratio: a critical determinant of myocardial contractility.
    Basic Res Cardiol. 1997;92 Suppl 1:17-24 PMID: 9202840
  24. Cardiac excitation-contraction coupling.
    Nature. 2002 Jan 10;415(6868):198-205 PMID: 11805843
  25. Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity.
    Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H1146-53 PMID: 14630633
  26. The alpha-helical propensity of the cytoplasmic domain of phospholamban: a molecular dynamics simulation of the effect of phosphorylation and mutation.
    Biophys J. 2005 May;88(5):3243-51 PMID: 15764655
  27. Sequence analysis of phospholamban. Identification of phosphorylation sites and two major structural domains.
    J Biol Chem. 1986 Oct 5;261(28):13333-41 PMID: 3759968
  28. Thyroid hormone-induced alterations in phospholamban protein expression. Regulatory effects on sarcoplasmic reticulum Ca2+ transport and myocardial relaxation.
    Circ Res. 1994 Aug;75(2):245-51 PMID: 8033338
  29. Complete complementary DNA-derived amino acid sequence of canine cardiac phospholamban.
    J Clin Invest. 1987 Jan;79(1):301-4 PMID: 3793929
  30. Sarcolipin regulates sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) by binding to transmembrane helices alone or in association with phospholamban.
    Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5040-5 PMID: 12692302
  31. Thyroid hormone regulation of calcium cycling proteins.
    Thyroid. 2002 Jun;12(6):453-7 PMID: 12165106
  32. Phospholamban: protein structure, mechanism of action, and role in cardiac function.
    Physiol Rev. 1998 Oct;78(4):921-47 PMID: 9790566
  33. Phospholamban domain I/cytochrome b5 transmembrane sequence chimeras do not inhibit SERCA2a.
    FEBS Lett. 1998 Apr 3;425(3):509-12 PMID: 9563523
  34. Sarcolipin inhibits polymerization of phospholamban to induce superinhibition of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs).
    J Biol Chem. 2002 Jul 26;277(30):26725-8 PMID: 12032137
  35. Differential phospholamban gene expression in murine cardiac compartments. Molecular and physiological analyses.
    Circ Res. 1995 Aug;77(2):342-53 PMID: 7542181
  36. Expression and site-specific mutagenesis of phospholamban. Studies of residues involved in phosphorylation and pentamer formation.
    J Biol Chem. 1989 Aug 5;264(22):12950-5 PMID: 2502544
  37. Overexpression of sarcolipin decreases myocyte contractility and calcium transient.
    Cardiovasc Res. 2005 Jan 1;65(1):177-86 PMID: 15621045
  38. Characterization of the gene encoding human sarcolipin (SLN), a proteolipid associated with SERCA1: absence of structural mutations in five patients with Brody disease.
    Genomics. 1997 Nov 1;45(3):541-53 PMID: 9367679
  39. Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation.
    Circ Res. 1994 Sep;75(3):401-9 PMID: 8062415
  40. Structure and orientation of sarcolipin in lipid environments.
    Biochemistry. 2002 Jan 15;41(2):475-82 PMID: 11781085
  41. Reversal of phospholamban-induced inhibition of cardiac sarcoplasmic reticulum Ca(2+)-ATPase by tannin.
    Biochem Biophys Res Commun. 1994 Aug 15;202(3):1668-73 PMID: 8060355
  42. Sarcolipin, the "proteolipid" of skeletal muscle sarcoplasmic reticulum, is a unique, amphipathic, 31-residue peptide.
    Arch Biochem Biophys. 1992 Nov 1;298(2):620-3 PMID: 1416990
  43. Corticosteroids decrease mRNA levels of SERCA pumps, whereas they increase sarcolipin mRNA in the rat diaphragm.
    J Physiol. 2000 Apr 15;524 Pt 2:387-97 PMID: 10766920
  44. Purification and properties of an adenosine triphosphatase from sarcoplasmic reticulum.
    J Biol Chem. 1970 Sep 10;245(17):4508-18 PMID: 4250726
  45. Down-regulation of sarcolipin mRNA expression in chronic atrial fibrillation.
    Eur J Clin Invest. 2004 Nov;34(11):723-30 PMID: 15530144
  46. The transgenic expression of highly inhibitory monomeric forms of phospholamban in mouse heart impairs cardiac contractility.
    J Biol Chem. 2000 May 19;275(20):14985-91 PMID: 10809743
  47. Sarcolipin, the shorter homologue of phospholamban, forms oligomeric structures in detergent micelles and in liposomes.
    J Biol Chem. 2001 Aug 17;276(33):30845-52 PMID: 11413134
  48. Sarcoplasmic reticulum gene expression in cardiac hypertrophy and heart failure.
    Circ Res. 1994 Apr;74(4):555-64 PMID: 8137493
  49. The regulation of SERCA-type pumps by phospholamban and sarcolipin.
    Ann N Y Acad Sci. 2003 Apr;986:472-80 PMID: 12763867
  50. Phospholamban modulates murine atrial contractile parameters and responses to beta-adrenergic agonists.
    J Mol Cell Cardiol. 1998 Jul;30(7):1275-84 PMID: 9710796
  51. Targeted overexpression of sarcolipin in the mouse heart decreases sarcoplasmic reticulum calcium transport and cardiac contractility.
    J Biol Chem. 2006 Feb 17;281(7):3972-9 PMID: 16365042
  52. New perspectives on the role of SERCA2's Ca2+ affinity in cardiac function.
    Biochim Biophys Acta. 2006 Nov;1763(11):1216-28 PMID: 17005265
  53. Phospholamban expressed in slow-twitch and chronically stimulated fast-twitch muscles minimally affects calcium affinity of sarcoplasmic reticulum Ca(2+)-ATPase.
    J Biol Chem. 1992 Dec 25;267(36):26056-61 PMID: 1464616
  54. Calcium content of the sarcoplasmic reticulum in isolated ventricular myocytes from patients with terminal heart failure.
    J Mol Cell Cardiol. 1998 Apr;30(4):743-9 PMID: 9602423
  55. cAMP and calcium-dependent mechanisms of phospholamban phosphorylation in intact hearts.
    Am J Physiol. 1990 Feb;258(2 Pt 2):H318-25 PMID: 1689964
  56. Phosphorylation of the sarcoplasmic reticulum and sarcolemma.
    Annu Rev Physiol. 1982;44:401-23 PMID: 6280588
  57. Cardiac-specific overexpression of sarcolipin in phospholamban null mice impairs myocyte function that is restored by phosphorylation.
    Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2446-51 PMID: 16461894
  58. Physical interactions between phospholamban and sarco(endo)plasmic reticulum Ca2+-ATPases are dissociated by elevated Ca2+, but not by phospholamban phosphorylation, vanadate, or thapsigargin, and are enhanced by ATP.
    J Biol Chem. 2000 May 19;275(20):15034-8 PMID: 10809745
  59. Sarcolipin uncouples hydrolysis of ATP from accumulation of Ca2+ by the Ca2+-ATPase of skeletal-muscle sarcoplasmic reticulum.
    Biochem J. 2002 Jan 15;361(Pt 2):277-86 PMID: 11772399
  60. Structure of the rabbit phospholamban gene, cloning of the human cDNA, and assignment of the gene to human chromosome 6.
    J Biol Chem. 1991 Jun 25;266(18):11669-75 PMID: 1828805
  61. Functional Co-expression of the canine cardiac Ca2+ pump and phospholamban in Spodoptera frugiperda (Sf21) cells reveals new insights on ATPase regulation.
    J Biol Chem. 1997 Jun 20;272(25):15872-80 PMID: 9188486
  62. Mechanism by which cyclic adenosine 3':5'-monophosphate-dependent protein kinase stimulates calcium transport in cardiac sarcoplasmic reticulum.
    Circ Res. 1979 Mar;44(3):384-91 PMID: 216505
  63. beta-Adrenergic stimulation of phospholamban phosphorylation and Ca2+-ATPase activity in guinea pig ventricles.
    J Biol Chem. 1983 Jan 10;258(1):464-71 PMID: 6217205
  64. Is depressed myocyte contractility centrally involved in heart failure?
    Circ Res. 2003 Mar 7;92(4):350-8 PMID: 12623873
  65. Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation-contraction coupling in the heart.
    Cardiovasc Res. 2007 Mar 1;73(4):631-40 PMID: 17157285
  66. Phospholamban: a crucial regulator of cardiac contractility.
    Nat Rev Mol Cell Biol. 2003 Jul;4(7):566-77 PMID: 12838339
  67. Functional interplay between dual site phospholambam phosphorylation: insights from genetically altered mouse models.
    Basic Res Cardiol. 2002;97 Suppl 1:I43-8 PMID: 12479233
  68. Dependence of cardiac sarcoplasmic reticulum calcium pump activity on the phosphorylation status of phospholamban.
    J Biol Chem. 1991 Sep 15;266(26):17486-93 PMID: 1832673
  69. Regulation of sarco(endo)plasmic reticulum Ca2+ adenosine triphosphatase by phospholamban and sarcolipin: implication for cardiac hypertrophy and failure.
    Trends Cardiovasc Med. 2003 May;13(4):152-7 PMID: 12732449
  70. Post-transcriptional downregulation of sarcolipin mRNA by triiodothyronine in the atrial myocardium.
    FEBS Lett. 2006 Apr 17;580(9):2247-52 PMID: 16566928
  71. Regulation of myocardial Ca2+-ATPase and phospholamban mRNA expression in response to pressure overload and thyroid hormone.
    Proc Natl Acad Sci U S A. 1989 Apr;86(8):2966-70 PMID: 2523077
  72. Effects of isoproterenol on twitch contraction of wild type and phospholamban-deficient murine ventricular myocardium.
    J Mol Cell Cardiol. 1999 Jan;31(1):159-66 PMID: 10072724
  73. A single site (Ser16) phosphorylation in phospholamban is sufficient in mediating its maximal cardiac responses to beta -agonists.
    J Biol Chem. 2000 Dec 8;275(49):38938-43 PMID: 10988285
  74. Molecular regulation of phospholamban function and expression.
    Trends Cardiovasc Med. 1998 Nov;8(8):330-40 PMID: 14987547
  75. Cardiac-specific overexpression of phospholamban alters calcium kinetics and resultant cardiomyocyte mechanics in transgenic mice.
    J Clin Invest. 1996 Jan 15;97(2):533-9 PMID: 8567978
  76. Phospholamban inhibitory function is activated by depolymerization.
    J Biol Chem. 1997 Jun 13;272(24):15061-4 PMID: 9182523
  77. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.
    Science. 2003 Feb 28;299(5611):1410-3 PMID: 12610310
  78. Effect of thyroid hormone on the expression of mRNA encoding sarcoplasmic reticulum proteins.
    Circ Res. 1991 Aug;69(2):266-76 PMID: 1830516
  79. Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice.
    Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9199-204 PMID: 15201433
  80. Sites of regulatory interaction between calcium ATPases and phospholamban.
    Ann N Y Acad Sci. 1998 Sep 16;853:31-42 PMID: 10603934
  81. Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human.
    J Clin Invest. 2003 Mar;111(6):869-76 PMID: 12639993
Article Info
Journal
Journal of molecular and cellular cardiology
Abbr.
J Mol Cell Cardiol
ISSN
0022-2828
DOI
10.1016/j.yjmcc.2007.03.738
Published
2007-05-00
Epub
2007-00-12
Pages
903-11
Language
English
Region
England
NLM ID
0262322
PMCID
PMC2743185
Subset
IM
Grants
NHLBI NIH HHS · R01 HL088555-01A1 · United States
NHLBI NIH HHS · R01 HL088555 · United States
NHLBI NIH HHS · R01 HL064140 · United States
NHLBI NIH HHS · R01 HL064140-09 · United States
NHLBI NIH HHS · R01-HL64140 · United States
External Links
PubMed source DOI: 10.1016/j.yjmcc.2007.03.738 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2