Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
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 language | English |
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Article number | 13 |
Journal | Basic research in cardiology |
Volume | 114 |
Issue number | 2 |
Publication status | Published - 1 Mar 2019 |
Peer-reviewed | Yes |
External IDs
PubMed | 30788598 |
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ORCID | /0000-0003-2514-9429/work/151982629 |
Keywords
ASJC Scopus subject areas
Keywords
- Calcium cycling, CaMKII, Late sodium current, PKA, PP1, PP2A, SR calcium leak