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

Y. Yang, Tao Guo, Tetsuro Oda, Asima Chakraborty, L. Chen, Hitoshi Uchinoumi, Anne A Knowlton, Bradley R. Fruen, Razvan L. Cornea, Gerhard Meissner, Donald M Bers

Research output: Chapter in Book/Report/Conference proceedingChapter

46 Scopus citations

Abstract

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. 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. 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). 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.

Original languageEnglish (US)
Title of host publicationCirculation research
Pages295-306
Number of pages12
Volume114
Edition2
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Yang, Y., Guo, T., Oda, T., Chakraborty, A., Chen, L., Uchinoumi, H., Knowlton, A. A., Fruen, B. R., Cornea, R. L., Meissner, G., & Bers, D. M. (2014). Cardiac myocyte Z-line calmodulin is mainly RyR2-bound, and reduction is arrhythmogenic and occurs in heart failure. In Circulation research (2 ed., Vol. 114, pp. 295-306) https://doi.org/10.1161/CIRCRESAHA.114.302857