Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Jörg Eiringhaus - , University of Göttingen, Hannover Medical School (MHH), Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Jonas Herting - , University of Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Felix Schatter - , University of Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Viacheslav O. Nikolaev - , University of Hamburg (Author)
  • Julia Sprenger - , University of Göttingen (Author)
  • Yansong Wang - , European Molecular Biology Laboratory (EMBL) Heidelberg (Author)
  • Maja Köhn - , European Molecular Biology Laboratory (EMBL) Heidelberg, University of Freiburg (Author)
  • Markus Zabel - , University of Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Ali El-Armouche - , Institute of Pharmacology and Toxicology, TUD Dresden University of Technology (Author)
  • Gerd Hasenfuss - , University of Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Samuel Sossalla - , University of Göttingen, University of Regensburg, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Thomas H. Fischer - , University of Göttingen, Klinikum Coburg, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)

Abstract

Increased late sodium current (late I Na ) is an important arrhythmogenic trigger in cardiac disease. It prolongs cardiac action potential and leads to an increased SR Ca 2+ leak. This study investigates the contribution of Ca 2+ /Calmodulin-dependent kinase II (CaMKII), protein kinase A (PKA) and conversely acting protein phosphatases 1 and 2A (PP1, PP2A) to this subcellular crosstalk. Augmentation of late I Na (ATX-II) in murine cardiomyocytes led to an increase of diastolic Ca 2+ spark frequency and amplitudes of Ca 2+ transients but did not affect SR Ca 2+ load. Interestingly, inhibition of both, CaMKII and PKA, attenuated the late I Na -dependent induction of the SR Ca 2+ leak. PKA inhibition additionally reduced the amplitudes of systolic Ca 2+ transients. FRET-measurements revealed increased levels of cAMP upon late I Na augmentation, which could be prevented by simultaneous inhibition of Na + /Ca 2+ -exchanger (NCX) suggesting that PKA is activated by Ca 2+ -dependent cAMP-production. Whereas inhibition of PP2A showed no effect on late I Na -dependent alterations of Ca 2+ cycling, additional inhibition of PP1 further increased the SR Ca 2+ leak. In line with this, selective activation of PP1 yielded a strong reduction of the late I Na -induced SR Ca 2+ leak and did not affect systolic Ca 2+ release. This study indicates that phosphatase/kinase-balance is perturbed upon increased Na + influx leading to disruption of ventricular Ca 2+ cycling via CaMKII- and PKA-dependent pathways. Importantly, an activation of PP1 at RyR2 may represent a promising new toehold to counteract pathologically increased kinase activity.

Details

Original languageEnglish
Article number13
JournalBasic research in cardiology
Volume114
Issue number2
Publication statusPublished - 1 Mar 2019
Peer-reviewedYes

External IDs

PubMed 30788598
ORCID /0000-0003-2514-9429/work/151982629

Keywords

Keywords

  • Calcium cycling, CaMKII, Late sodium current, PKA, PP1, PP2A, SR calcium leak