title: Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure.
abstract: BACKGROUND
  approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca(2+) release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca(2+) remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca(2+)/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias.
  
  
  RESULTS
  mice in which the S2814 Ca(2+)/calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca(2+) release events, resulting in reduced sarcoplasmic reticulum Ca(2+) load on confocal microscopy. These Ca(2+) release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts without arrhythmias; however, they develop sustained ventricular tachycardia and sudden cardiac death on catecholaminergic provocation by caffeine/epinephrine or programmed electric stimulation. Young S2814D mice have a significant predisposition to sudden arrhythmogenic death after transverse aortic constriction surgery. Finally, genetic ablation of the Ca(2+)/calmodulin-dependent protein kinase II site on RyR2 (S2814A) protects mutant mice from pacing-induced arrhythmias versus wild-type mice after transverse aortic constriction surgery.
  
  
  CONCLUSIONS
  our results suggest that Ca(2+)/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca(2+) release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, BCM335, Houston, TX 77030, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: van Oort
authors.forename: Mark D
authors.initials: MD
authors.lastname: McCauley
authors.forename: Sayali S
authors.initials: SS
authors.lastname: Dixit
authors.forename: Laetitia
authors.initials: L
authors.lastname: Pereira
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Respress
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.forename: Angela C
authors.initials: AC
authors.lastname: De Almeida
authors.forename: Darlene G
authors.initials: DG
authors.lastname: Skapura
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000453:epidemiology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D016757:Death, Sudden, Cardiac / Q000453:epidemiology; D004558:Electric Stimulation; D006333:Heart Failure / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010766:Phosphorylation; D012307:Risk Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000453:epidemiology* / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium