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

Standard

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

in: BASIC RES CARDIOL, Jahrgang 114, Nr. 2, 20.02.2019, S. 13.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Eiringhaus, J, Herting, J, Schatter, F, Nikolaev, VO, Sprenger, J, Wang, Y, Köhn, M, Zabel, M, El-Armouche, A, Hasenfuss, G, Sossalla, S & Fischer, TH 2019, 'Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling', BASIC RES CARDIOL, Jg. 114, Nr. 2, S. 13. https://doi.org/10.1007/s00395-019-0720-7

APA

Eiringhaus, J., Herting, J., Schatter, F., Nikolaev, V. O., Sprenger, J., Wang, Y., Köhn, M., Zabel, M., El-Armouche, A., Hasenfuss, G., Sossalla, S., & Fischer, T. H. (2019). Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling. BASIC RES CARDIOL, 114(2), 13. https://doi.org/10.1007/s00395-019-0720-7

Vancouver

Eiringhaus J, Herting J, Schatter F, Nikolaev VO, Sprenger J, Wang Y et al. Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling. BASIC RES CARDIOL. 2019 Feb 20;114(2):13. https://doi.org/10.1007/s00395-019-0720-7

Bibtex

@article{a763cf94152249629c0d3f4a24b58e4a,
title = "Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling",
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 = "Action Potentials/physiology, Animals, Calcium/metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism, Mice, Myocytes, Cardiac/metabolism, Protein Phosphatase 1/metabolism, Protein Phosphatase 2/metabolism, Sodium/metabolism",
author = "J{\"o}rg Eiringhaus and Jonas Herting and Felix Schatter and Nikolaev, {Viacheslav O} and Julia Sprenger and Yansong Wang and Maja K{\"o}hn and Markus Zabel and Ali El-Armouche and Gerd Hasenfuss and Samuel Sossalla and Fischer, {Thomas H}",
year = "2019",
month = feb,
day = "20",
doi = "10.1007/s00395-019-0720-7",
language = "English",
volume = "114",
pages = "13",
journal = "BASIC RES CARDIOL",
issn = "0300-8428",
publisher = "D. Steinkopff-Verlag",
number = "2",

}

RIS

TY - JOUR

T1 - Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling

AU - Eiringhaus, Jörg

AU - Herting, Jonas

AU - Schatter, Felix

AU - Nikolaev, Viacheslav O

AU - Sprenger, Julia

AU - Wang, Yansong

AU - Köhn, Maja

AU - Zabel, Markus

AU - El-Armouche, Ali

AU - Hasenfuss, Gerd

AU - Sossalla, Samuel

AU - Fischer, Thomas H

PY - 2019/2/20

Y1 - 2019/2/20

N2 - 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.

AB - 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.

KW - Action Potentials/physiology

KW - Animals

KW - Calcium/metabolism

KW - Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism

KW - Mice

KW - Myocytes, Cardiac/metabolism

KW - Protein Phosphatase 1/metabolism

KW - Protein Phosphatase 2/metabolism

KW - Sodium/metabolism

U2 - 10.1007/s00395-019-0720-7

DO - 10.1007/s00395-019-0720-7

M3 - SCORING: Journal article

C2 - 30788598

VL - 114

SP - 13

JO - BASIC RES CARDIOL

JF - BASIC RES CARDIOL

SN - 0300-8428

IS - 2

ER -