Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling
2019 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling
Eiringhaus, J. ; Herting, J. ; Schatter, F. ; Nikolaev, V. O. ; Sprenger, J.; Wang, Y. & Köhn, M. et al. (2019)
Basic Research in Cardiology, 114(2) pp. 13. DOI: https://doi.org/10.1007/s00395-019-0720-7
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- Authors
- Eiringhaus, Jörg ; Herting, Jonas ; Schatter, Felix ; Nikolaev, Viacheslav O. ; Sprenger, Julia; Wang, Yansong; Köhn, Maja; Zabel, Markus ; El-Armouche, Ali ; Hasenfuss, Gerd ; Sossalla, Samuel ; Fischer, Thomas H.
- 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.
- Issue Date
- 2019
- Journal
- Basic Research in Cardiology
- Project
- SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz
SFB 1002 | A11: Absolute Arrhythmie bei Vorhofflimmern - ein neuer Mechanismus, der zu einer Störung von Ca2+-Homöostase und elektrischer Stabilität in der Transition zur Herzinsuffizienz führt - Working Group
- RG El-Armouche
RG Hasenfuß (Transition zur Herzinsuffizienz)
RG Nikolaev (Cardiovascular Research Center)
RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)
RG T. Fischer - ISSN
- 0300-8428; 1435-1803
- eISSN
- 1435-1803
- Language
- English