HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Cardiac myocyte Z-line calmodulin is mainly RyR2-bound, and reduction is arrhythmogenic and occurs in heart failure.

AbstractRATIONALE:
Calmodulin (CaM) associates with cardiac ryanodine receptor type-2 (RyR2) as an important regulator. Defective CaM-RyR2 interaction may occur in heart failure, cardiac hypertrophy, and catecholaminergic polymorphic ventricular tachycardia. However, the in situ binding properties for CaM-RyR2 are unknown.
OBJECTIVE:
We sought to measure the in situ binding affinity and kinetics for CaM-RyR2 in normal and heart failure ventricular myocytes, estimate the percentage of Z-line-localized CaM that is RyR2-bound, and test cellular function of defective CaM-RyR2 interaction.
METHODS AND RESULTS:
Using fluorescence resonance energy transfer in permeabilized myocytes, we specifically resolved RyR2-bound CaM from other potential binding targets and measured CaM-RyR2 binding affinity in situ (Kd=10-20 nmol/L). Using RyR2(ADA/+) knock-in mice, in which half of the CaM-RyR2 binding is suppressed, we estimated that >90% of Z-line CaM is RyR2-bound. Functional tests indicated a higher propensity for Ca2+ wave production and stress-induced ventricular arrhythmia in RyR2(ADA/+) mice. In a post-myocardial infarction rat heart failure model, we detected a decrease in the CaM-RyR2 binding affinity (Kd≈51 nmol/L; ≈3-fold increase) and unaltered RyR2 affinity for the FK506-binding protein FKBP12.6 (Kd~0.8 nmol/L).
CONCLUSIONS:
CaM binds to RyR2 with high affinity in cardiac myocytes. Physiologically, CaM is bound to >70% of RyR2 monomers and inhibits sarcoplasmic reticulum Ca2+ release. RyR2 is the major binding site for CaM along the Z-line in cardiomyocytes, and dissociating CaM from RyR2 can cause severe ventricular arrhythmia. In heart failure, RyR2 shows decreased CaM affinity, but unaltered FKBP 12.6 affinity.
AuthorsYi Yang, Tao Guo, Tetsuro Oda, Asima Chakraborty, Le Chen, Hitoshi Uchinoumi, Anne A Knowlton, Bradley R Fruen, Razvan L Cornea, Gerhard Meissner, Donald M Bers
JournalCirculation research (Circ Res) Vol. 114 Issue 2 Pg. 295-306 (Jan 17 2014) ISSN: 1524-4571 [Electronic] United States
PMID24186966 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Calmodulin
  • Ryanodine Receptor Calcium Release Channel
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 1B
Topics
  • Animals
  • Arrhythmias, Cardiac (etiology, genetics, metabolism, physiopathology)
  • Calcium Signaling
  • Calmodulin (metabolism)
  • Disease Models, Animal
  • Fluorescence Resonance Energy Transfer
  • Heart Failure (complications, genetics, metabolism, physiopathology)
  • Kinetics
  • Mice
  • Mice, Transgenic
  • Myocytes, Cardiac (metabolism)
  • Protein Binding
  • Protein Interaction Mapping
  • Rats
  • Rats, Sprague-Dawley
  • Ryanodine Receptor Calcium Release Channel (genetics, metabolism)
  • Sarcoplasmic Reticulum (metabolism)
  • Tacrolimus Binding Proteins (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: