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Basic Res Cardiol. 2019 Feb 20;114(2):13. doi: 10.1007/s00395-019-0720-7.

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

Author information

1
Abt. Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
2
Abt. Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
3
Deutsches Zentrum für Herz-Kreislauf Forschung (DZHK), Standort Göttingen, Göttingen, Germany.
4
Institut für Experimentelle Herz-Kreislaufforschung, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
5
European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
6
Centre for Biological Signalling Studies (BIOSS) and Faculty of Biology, University of Freiburg, Freiburg, Germany.
7
Institut für Pharmakologie und Toxikologie, Technische Universität Dresden, Dresden, Germany.
8
Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany.
9
Abt. Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. thomas.fischer@med.uni-goettingen.de.
10
Medizinische Klinik II, Kardiologie, Angiologie, Pneumologie, Klinikum Coburg, Coburg, Germany. thomas.fischer@med.uni-goettingen.de.
11
Deutsches Zentrum für Herz-Kreislauf Forschung (DZHK), Standort Göttingen, Göttingen, Germany. thomas.fischer@med.uni-goettingen.de.

Abstract

Increased late sodium current (late INa) is an important arrhythmogenic trigger in cardiac disease. It prolongs cardiac action potential and leads to an increased SR Ca2+ leak. This study investigates the contribution of Ca2+/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 INa (ATX-II) in murine cardiomyocytes led to an increase of diastolic Ca2+ spark frequency and amplitudes of Ca2+ transients but did not affect SR Ca2+ load. Interestingly, inhibition of both, CaMKII and PKA, attenuated the late INa-dependent induction of the SR Ca2+ leak. PKA inhibition additionally reduced the amplitudes of systolic Ca2+ transients. FRET-measurements revealed increased levels of cAMP upon late INa augmentation, which could be prevented by simultaneous inhibition of Na+/Ca2+-exchanger (NCX) suggesting that PKA is activated by Ca2+-dependent cAMP-production. Whereas inhibition of PP2A showed no effect on late INa-dependent alterations of Ca2+ cycling, additional inhibition of PP1 further increased the SR Ca2+ leak. In line with this, selective activation of PP1 yielded a strong reduction of the late INa-induced SR Ca2+ leak and did not affect systolic Ca2+ release. This study indicates that phosphatase/kinase-balance is perturbed upon increased Na+ influx leading to disruption of ventricular Ca2+ 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.

KEYWORDS:

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

PMID:
30788598
DOI:
10.1007/s00395-019-0720-7

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