title: Inhibition of CaMKII phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 knockout mice.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Tiannan
authors.initials: T
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cutler
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenbaum
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006325:Heart Atria / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D021122:Protein Subunits; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; D000099211:Phospholamban; C509259:FKBP1B protein, mouse