Elevated local [Ca2+] and CaMKII promote spontaneous Ca2+ release in ankyrin-B-deficient hearts

Iuliana Popescu, Samuel Galice, Peter J. Mohler, Sanda Despa

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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) Ca2+ leak occurs through Ca2+ sparks in AnkB-deficient (AnkB+/-) mice, which may contribute to arrhythmogenicity via Ca2+ waves. Here, we investigated the mechanisms responsible for increased Ca2+ 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 Ca2+ 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 [Ca2+] in the junctional cleft caused by reduced Na+/Ca2+ exchange activity. Indeed, using the RyR-targeted Ca2+ sensor GCaMP2.2-FBKP12.6, we found that local junctional [Ca2+] is significantly elevated in AnkB+/- myocytes. Conclusions The increased incidence of pro-arrhythmogenic Ca2+ sparks and waves in AnkB+/- hearts is due to enhanced CaMKII-mediated RyR phosphorylation, which is caused by higher junctional [Ca2+] and consequent local CaMKII activation.

Original languageEnglish (US)
Pages (from-to)287-294
Number of pages8
JournalCardiovascular Research
Volume111
Issue number3
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

Keywords

  • Ankyrin-B
  • Ca sparks
  • CaMKII
  • Junctions
  • Local Ca concentration

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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