title: CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation.
abstract: BACKGROUND
  Although research suggests that diastolic Ca(2+) levels might be increased in atrial fibrillation (AF), this hypothesis has never been tested. Diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) might increase diastolic Ca(2+) levels and play a role in triggering or maintaining AF by transient inward currents through Na(+)/Ca(2+) exchange. In ventricular myocardium, ryanodine receptor type 2 (RyR2) phosphorylation by Ca(2+)/calmodulin-dependent protein kinase (CaMK)II is emerging as an important mechanism for SR Ca(2+) leak.
  
  
  OBJECTIVE
  We tested the hypothesis that CaMKII-dependent diastolic SR Ca(2+) leak and elevated diastolic Ca(2+) levels occurs in atrial myocardium of patients with AF.
  
  
  RESULTS
  We used isolated human right atrial myocytes from patients with AF versus sinus rhythm and found CaMKII expression to be increased by 40+/-14% (P<0.05), as well as CaMKII phosphorylation by 33+/-12% (P<0.05). This was accompanied by a significantly increased RyR2 phosphorylation at the CaMKII site (Ser2814) by 110+/-53%. Furthermore, cytosolic Ca(2+) levels were elevated during diastole (229+/-20 versus 164+/-8 nmol/L, P<0.05). Most likely, this resulted from an increased SR Ca(2+) leak in AF (P<0.05), which was not attributable to higher SR Ca(2+) load. Tetracaine experiments confirmed that SR Ca(2+) leak through RyR2 leads to the elevated diastolic Ca(2+) level. CaMKII inhibition normalized SR Ca(2+) leak and cytosolic Ca(2+) levels without changes in L-type Ca(2+) current.
  
  
  CONCLUSIONS
  Increased CaMKII-dependent phosphorylation of RyR2 leads to increased SR Ca(2+) leak in human AF, causing elevated cytosolic Ca(2+) levels, thereby providing a potential arrhythmogenic substrate that could trigger or maintain AF.
authors.affiliation: Department of Cardiology and Pneumology/Heart Center, Georg-August-University Göttingen, Robert-Koch-Strasse 40, Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Neef
authors.forename: Nataliya
authors.initials: N
authors.lastname: Dybkova
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
authors.forename: Katharina R
authors.initials: KR
authors.lastname: Ort
authors.forename: Nina
authors.initials: N
authors.lastname: Fluschnik
authors.forename: Kay
authors.initials: K
authors.lastname: Neumann
authors.forename: Ralf
authors.initials: R
authors.lastname: Seipelt
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Schöndube
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
mesh_terms: D000200:Action Potentials; D000779:Anesthetics, Local / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001596:Benzylamines / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016022:Case-Control Studies; D048429:Cell Size; D003971:Diastole; D006325:Heart Atria / Q000201:enzymology; D006801:Humans; D018613:Microscopy, Confocal; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013599:Systole; D013748:Tetracaine / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation; D000099211:Phospholamban; D000096926:Benzenesulfonamides
chemical_list: D000779:Anesthetics, Local; D001596:Benzylamines; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D047428:Protein Kinase Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D013449:Sulfonamides; D013748:Tetracaine; D000099211:Phospholamban; C072105:KN 93; D000096926:Benzenesulfonamides; C506946:ATP2A2 protein, human