Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice.
A trial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca2+ handling. Diastolic Ca2+ release from the sarcoplasmic reticulum via "leaky" ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice. Rapid atrial pacing resulted in increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2, while both pharmacologic and genetic inhibition of CaMKII prevented AF inducibility in Ryr2R176Q/+ mice. This result suggests that AF requires both an arrhythmogenic substrate (e.g., RyR2 mutation) and enhanced CaMKII activity. Increased CaMKII phosphorylation of RyR2 was observed in atrial biopsies from mice with atrial enlargement and spontaneous AF, goats with lone AF, and patients with chronic AF. Genetic inhibition of CaMKII phosphorylation of RyR2 in Ryr2S2814A knockin mice reduced AF inducibility in a vagotonic AF model. Together, these findings suggest that increased RyR2-dependent Ca2+ leakage due to enhanced CaMKII activity is an important downstream effect of CaMKII in individuals susceptible to AF induction.
Chelu
Mihail G
MG
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA.
Sarma
Satyam
S
Sood
Subeena
S
Wang
Sufen
S
van Oort
Ralph J
RJ
Skapura
Darlene G
DG
Li
Na
N
Santonastasi
Marco
M
Müller
Frank Ulrich
FU
Schmitz
Wilhelm
W
Schotten
Ulrich
U
Anderson
Mark E
ME
Valderrábano
Miguel
M
Dobrev
Dobromir
D
Wehrens
Xander H T
XH
D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002304:Cardiac Pacing, Artificial; D051786:Cyclic AMP Response Element Modulator / Q000502:physiology; D004562:Electrocardiography; D006041:Goats; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000502:physiology; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
C527819:AC3-I peptide; C497411:Crem protein, mouse; D010455:Peptides; D019837:Ryanodine Receptor Calcium Release Channel; D051786:Cyclic AMP Response Element Modulator; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium