Eiringhaus, Joerg and Herting, Jonas and Schatter, Felix and Nikolaev, Viacheslav O. and Sprenger, Julia and Wang, Yansong and Koehn, Maja and Zabel, Markus and El-Armouche, Ali and Hasenfuss, Gerd and Sossalla, Samuel and Fischer, Thomas H. (2019) Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling. BASIC RESEARCH IN CARDIOLOGY, 114 (2): 13. ISSN 0300-8428, 1435-1803
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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 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 I-Na (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 I-Na-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 I-Na 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 I-Na-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 I-Na-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LATE I-NA; RETICULUM CA2+ LEAK; KINASE-II; HEART; CAMKII; PHOSPHATASE-1; CONTRACTILITY; RANOLAZINE; MYOCARDIUM; MECHANISM; Late sodium current; SR calcium leak; Calcium cycling; CaMKII; PKA; PP1; PP2A |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Apr 2020 12:29 |
| Last Modified: | 16 Apr 2020 12:29 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27497 |
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