Home LiteratureArticle Details
PMID: 16481613 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Analysis of calstabin2 (FKBP12.6)-ryanodine receptor interactions: rescue of heart failure by calstabin2 in mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 9 ·2006-02-28 ·Pages 3456-61

Huang F, Shan J, Reiken S, Wehrens XH, Marks AR

Abstract

The ryanodine receptor (RyR)/calcium-release channel on the sarcoplasmic reticulum mediates intracellular calcium release required for striated muscle contraction. RyR2, the predominant isoform in cardiac myocytes, comprises a macromolecular complex that includes calstabin2 (FKBP12.6). Calstabin2, an 11.8-kDa cis-trans peptidyl-prolyl isomerase (apparent molecular mass 12.6 kDa), stabilizes the closed state of the RyR2 channel, but the mechanism by which it achieves this regulation is not fully understood. Protein kinase A (PKA) phosphorylation of RyR2 decreases the affinity of calstabin2 for the RyR2 channel complex. In the present study we identified key aspartic acid residues on calstabin2 that are involved in binding to RyR2 and likely play a role in PKA phosphorylation-induced dissociation of calstabin2 from RyR2. We show that a mutant calstabin2 in which a key negatively charged residue (Asp-37) has been neutralized binds to a mutant RyR2 channel that mimics constitutively PKA-phosphorylated RyR2 (RyR2-S2808D). Furthermore, using wild-type and genetically altered murine models of heart failure induced by myocardial infarction, we show that manipulating the stoichiometry between calstabin2 and RyR2 can restore normal cardiac function in vivo.

MeSH Terms
Animals Aspartic Acid/genetics,metabolism Catalysis Disease Models, Animal Electrophysiology Gene Expression Regulation Mice Mice, Transgenic Models, Molecular Mutation/genetics Myocardial Infarction/genetics,metabolism,pathology,physiopathology Patch-Clamp Techniques Phosphorylation Protein Binding Protein Kinases/metabolism Protein Structure, Tertiary Ryanodine Receptor Calcium Release Channel/genetics,metabolism Serine/genetics,metabolism Static Electricity Structural Homology, Protein Tacrolimus Binding Protein 1A/chemistry,genetics,metabolism Tacrolimus Binding Proteins/chemistry,genetics,metabolism
Chemicals
FKBP12.6 protein, mouse Ryanodine Receptor Calcium Release Channel Aspartic Acid Serine Protein Kinases Tacrolimus Binding Protein 1A Tacrolimus Binding Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Huang Fannie
Clyde and Helen Wu Center for Molecular Cardiology, Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Shan Jian
Reiken Steven
Wehrens Xander H T
Marks Andrew R
References (33)
33 references, click to expand
  1. Structure of FKBP12.6 in complex with rapamycin.
    Acta Crystallogr D Biol Crystallogr. 2000 Mar;56(Pt 3):266-71 PMID: 10713512
  2. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein.
    Cell. 1994 May 20;77(4):513-23 PMID: 7514503
  3. Disruption of the myocardial extracellular matrix leads to cardiac dysfunction.
    J Clin Invest. 2000 Oct;106(7):857-66 PMID: 11018073
  4. FKBP12 binding modulates ryanodine receptor channel gating.
    J Biol Chem. 2001 May 18;276(20):16931-5 PMID: 11279144
  5. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure).
    J Am Coll Cardiol. 2001 Dec;38(7):2101-13 PMID: 11738322
  6. Regulation of ryanodine receptors via macromolecular complexes: a novel role for leucine/isoleucine zippers.
    Trends Cardiovasc Med. 2002 May;12(4):166-70 PMID: 12069756
  7. Localization of the 12.6-kDa FK506-binding protein (FKBP12.6) binding site to the NH2-terminal domain of the cardiac Ca2+ release channel (ryanodine receptor).
    J Biol Chem. 2003 Feb 7;278(6):3786-92 PMID: 12446682
  8. A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure.
    Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H1035-42 PMID: 12433661
  9. PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure.
    J Cell Biol. 2003 Mar 17;160(6):919-28 PMID: 12629052
  10. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death.
    Cell. 2003 Jun 27;113(7):829-40 PMID: 12837242
  11. Characterization of recombinant skeletal muscle (Ser-2843) and cardiac muscle (Ser-2809) ryanodine receptor phosphorylation mutants.
    J Biol Chem. 2003 Dec 19;278(51):51693-702 PMID: 14532276
  12. Protein kinase A phosphorylation at serine-2808 of the cardiac Ca2+-release channel (ryanodine receptor) does not dissociate 12.6-kDa FK506-binding protein (FKBP12.6).
    Circ Res. 2004 Mar 5;94(4):487-95 PMID: 14715536
  13. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2.
    Science. 2004 Apr 9;304(5668):292-6 PMID: 15073377
  14. N-terminal region of FKBP12 is essential for binding to the skeletal ryanodine receptor.
    J Biol Chem. 2004 Jun 18;279(25):26481-8 PMID: 15033987
  15. RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR).
    Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):13062-7 PMID: 15322274
  16. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin.
    Nature. 1989 Oct 26;341(6244):755-7 PMID: 2477714
  17. A practical guide to the preparation of Ca2+ buffers.
    Methods Cell Biol. 1994;40:3-29 PMID: 8201981
  18. Characterization of an exchange reaction between soluble FKBP-12 and the FKBP.ryanodine receptor complex. Modulation by FKBP mutants deficient in peptidyl-prolyl isomerase activity.
    J Biol Chem. 1995 Feb 10;270(6):2451-9 PMID: 7531689
  19. FK506 binding protein mutational analysis. Defining the surface residue contributions to stability of the calcineurin co-complex.
    J Biol Chem. 1995 Aug 11;270(32):18935-40 PMID: 7642551
  20. A novel FK506 binding protein can mediate the immunosuppressive effects of FK506 and is associated with the cardiac ryanodine receptor.
    J Biol Chem. 1995 Nov 3;270(44):26511-22 PMID: 7592869
  21. Effects of rapamycin on ryanodine receptor/Ca(2+)-release channels from cardiac muscle.
    Circ Res. 1996 Jun;78(6):990-7 PMID: 8635249
  22. Comparative mutational analysis of peptidyl prolyl cis/trans isomerases: active sites of Escherichia coli trigger factor and human FKBP12.
    FEBS Lett. 1997 Apr 28;407(2):184-90 PMID: 9166896
  23. Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12.
    Cell. 1999 Feb 5;96(3):425-36 PMID: 10025408
  24. Three amino acid residues determine selective binding of FK506-binding protein 12.6 to the cardiac ryanodine receptor.
    J Biol Chem. 1999 May 28;274(22):15315-9 PMID: 10336416
  25. Interaction of FKBP12.6 with the cardiac ryanodine receptor C-terminal domain.
    J Biol Chem. 2005 Feb 18;280(7):5475-85 PMID: 15591045
  26. Intracellular calcium release and cardiac disease.
    Annu Rev Physiol. 2005;67:69-98 PMID: 15709953
  27. Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure.
    Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9607-12 PMID: 15972811
  28. Molecular cloning and characterization of the ryanodine receptor/junctional channel complex cDNA from skeletal muscle sarcoplasmic reticulum.
    Proc Natl Acad Sci U S A. 1989 Nov;86(22):8683-7 PMID: 2813419
  29. Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium.
    Circulation. 1990 Aug;82(2 Suppl):I12-25 PMID: 2164894
  30. PPIase catalysis by human FK506-binding protein proceeds through a conformational twist mechanism.
    J Biol Chem. 1992 Feb 15;267(5):3316-24 PMID: 1371117
  31. FK506 binding protein associated with the calcium release channel (ryanodine receptor).
    J Biol Chem. 1992 May 15;267(14):9474-7 PMID: 1374404
  32. Characterization of high molecular weight FK-506 binding activities reveals a novel FK-506-binding protein as well as a protein complex.
    J Biol Chem. 1992 Oct 25;267(30):21753-60 PMID: 1383226
  33. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts.
    Cell. 2000 May 12;101(4):365-76 PMID: 10830164
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0511282103
Published
2006-02-28
Epub
2006-00-15
Pages
3456-61
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1413925
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0511282103 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