| First Author | Stokke MK | Year | 2011 |
| Journal | Cardiovasc Res | Volume | 90 |
| Issue | 3 | Pages | 503-12 |
| PubMed ID | 21242164 | Mgi Jnum | J:186007 |
| Mgi Id | MGI:5430724 | Doi | 10.1093/cvr/cvr013 |
| Citation | Stokke MK, et al. (2011) Ca(2+) wave probability is determined by the balance between SERCA2-dependent Ca(2+) reuptake and threshold SR Ca(2+) content. Cardiovasc Res 90(3):503-12 |
| abstractText | AIMS: In this manuscript, we determined the roles of the sarcoendoplasmic reticulum Ca(2+) ATPase 2 (SERCA2) and the ryanodine receptor (RyR) in Ca(2+) wave development during beta-adrenergic stimulation. METHODS AND RESULTS: SERCA2 knockout mice (KO) were used 6 days after cardio-specific gene deletion, with left ventricular SERCA2a abundance reduced by 54 +/- 9% compared with SERCA2(flox/flox) controls (FF) (P < 0.05). Ca(2+) waves occurred in fewer KO than FF myocytes (40 vs. 68%, P < 0.05), whereas the addition of isoproterenol (ISO) induced waves in an equal percentage of myocytes (82 vs. 64%). SERCA2-dependent Ca(2+) reuptake was slower in KO (-ISO, KO vs. FF: 15.4 +/- 1.2 vs. 21.1 +/- 1.4 s(-1), P < 0.05), but equal during ISO (+ISO, KO vs. FF: 21.9 +/- 3.3 vs. 27.7 +/- 2.7 s(-1)). Threshold SR Ca(2+) content for wave development was lower in KO (-ISO, KO vs. FF: 126.6 +/- 10.3 vs. 159.3 +/- 7.1 micromol/L, P < 0.05) and was increased by ISO only in FF (+ISO, KO vs. FF: 131.7 +/- 8.7 vs. 205.5 +/- 20.4 micromol/L, P < 0.05). During ISO, Ca(2+)/calmodulin-dependent kinase II (CaMKII)-dependent phosphorylation of RyR in KO was 217 +/- 21% of FF (P < 0.05), and SR Ca(2+) leak indicated higher RyR open probability in KO. CaMKII inhibition decreased Ca(2+) spark frequency in KO by 44% (P < 0.05) but not in FF. Mathematical modelling predicted that increased Ca(2+) sensitivity of RyR in KO could account for increased Ca(2+) wave probability during ISO. CONCLUSIONS: In ventricular cardiomyocytes with reduced SERCA2 abundance, Ca(2+) wave development following beta-adrenergic stimulation is potentiated. We suggest that this is caused by a CaMKII-dependent shift in the balance between SERCA2-dependent Ca(2+) reuptake and threshold SR Ca(2+) content. |
