Inhibition of CaMKII phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 knockout mice

Circ Res. 2012 Feb 3;110(3):465-70. doi: 10.1161/CIRCRESAHA.111.253229. Epub 2011 Dec 8.


Rationale: Abnormal calcium release from sarcoplasmic reticulum (SR) is considered an important trigger of atrial fibrillation (AF). Whereas increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity has been proposed to contribute to SR leak and AF induction, downstream targets of CaMKII remain controversial.

Objective: To test the hypothesis that inhibition of CaMKII-phosphorylated type-2 ryanodine receptors (RyR2) prevents AF initiation in FKBP12.6-deficient (-/-) mice.

Methods and results: Mice lacking RyR2-stabilizing subunit FKBP12.6 had a higher incidence of spontaneous and pacing-induced AF compared with wild-type mice. Atrial myocytes from FKBP12.6-/- mice exhibited spontaneous Ca(2+) waves (SCaWs) leading to Na(+)/Ca(2+)-exchanger activation and delayed afterdepolarizations (DADs). Mutation S2814A in RyR2, which inhibits CaMKII phosphorylation, reduced Ca(2+) spark frequency, SR Ca(2+) leak, and DADs in atrial myocytes from FKBP12.6-/-:S2814A mice compared with FKBP12.6-/- mice. Moreover, FKBP12.6-/-:S2814A mice exhibited a reduced susceptibility to inducible AF, whereas FKBP12.6-/-:S2808A mice were not protected from AF.

Conclusions: FKBP12.6 mice exhibit AF caused by SR Ca(2+) leak, Na(+)/Ca(2+)-exchanger activation, and DADs, which promote triggered activity. Genetic inhibition of RyR2-S2814 phosphorylation prevents AF induction in FKBP12.6-/- mice by suppressing SR Ca(2+) leak and DADs. These results suggest suppression of RyR2-S2814 phosphorylation as a potential anti-AF therapeutic target.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / prevention & control*
  • Calcium / metabolism
  • Calcium-Binding Proteins / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Heart Atria / cytology
  • Mice
  • Mice, Knockout
  • Models, Animal
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Patch-Clamp Techniques
  • Phosphorylation
  • Protein Subunits / deficiency
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Ryanodine Receptor Calcium Release Channel / genetics*
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sarcoplasmic Reticulum / metabolism
  • Tacrolimus Binding Proteins / deficiency*
  • Tacrolimus Binding Proteins / genetics*
  • Tacrolimus Binding Proteins / metabolism


  • Calcium-Binding Proteins
  • FKBP12.6 protein, mouse
  • Protein Subunits
  • Ryanodine Receptor Calcium Release Channel
  • phospholamban
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Tacrolimus Binding Proteins
  • Calcium