| First Author | Popescu I | Year | 2016 |
| Journal | Cardiovasc Res | Volume | 111 |
| Issue | 3 | Pages | 287-94 |
| PubMed ID | 27131508 | Mgi Jnum | J:253370 |
| Mgi Id | MGI:6107819 | Doi | 10.1093/cvr/cvw093 |
| Citation | Popescu I, et al. (2016) Elevated local [Ca2+] and CaMKII promote spontaneous Ca2+ release in ankyrin-B-deficient hearts. Cardiovasc Res 111(3):287-94 |
| abstractText | AIMS: Loss-of-function mutations in the cytoskeletal protein ankyrin-B (AnkB) cause ventricular tachyarrhythmias in humans. Previously, we found that a larger fraction of the sarcoplasmic reticulum (SR) Ca(2+) leak occurs through Ca(2+) sparks in AnkB-deficient (AnkB(+/-)) mice, which may contribute to arrhythmogenicity via Ca(2+) waves. Here, we investigated the mechanisms responsible for increased Ca(2+) spark frequency in AnkB(+/-) hearts. METHODS AND RESULTS: Using immunoblots and phospho-specific antibodies, we found that phosphorylation of ryanodine receptors (RyRs) by CaMKII is enhanced in AnkB(+/-) hearts. In contrast, the PKA-mediated RyR phosphorylation was comparable in AnkB(+/-) and wild-type (WT) mice. CaMKII inhibition greatly reduced Ca(2+) spark frequency in myocytes from AnkB(+/-) mice but had little effect in the WT. Global activities of the major phosphatases PP1 and PP2A were similar in AnkB(+/-) and WT hearts, while CaMKII autophosphorylation, a marker of CaMKII activation, was increased in AnkB(+/-) hearts. Thus, CaMKII-dependent RyR hyperphosphorylation in AnkB(+/-) hearts is caused by augmented CaMKII activity. Intriguingly, CaMKII activation is limited to the sarcolemma-SR junctions since non-junctional CaMKII targets (phospholamban, HDAC4) are not hyperphosphorylated in AnkB(+/-) myocytes. This local CaMKII activation may be the consequence of elevated [Ca(2+)] in the junctional cleft caused by reduced Na(+)/Ca(2+) exchange activity. Indeed, using the RyR-targeted Ca(2+) sensor GCaMP2.2-FBKP12.6, we found that local junctional [Ca(2+)] is significantly elevated in AnkB(+/-) myocytes. CONCLUSIONS: The increased incidence of pro-arrhythmogenic Ca(2+) sparks and waves in AnkB(+/-) hearts is due to enhanced CaMKII-mediated RyR phosphorylation, which is caused by higher junctional [Ca(2+)] and consequent local CaMKII activation. |
