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cAMP Imaging at Ryanodine Receptors Reveals β 2-Adrenoceptor Driven Arrhythmias

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cAMP Imaging at Ryanodine Receptors Reveals β 2-Adrenoceptor Driven Arrhythmias. / Berisha, Filip; Götz, Konrad R.; Wegener, J.; Brandenburg, Sören; Subramanian, Hariharan; Molina, Cristina; Rüffer, André; Petersen, Johannes; Bernhardt, Alexander; Girdauskas, Evaldas; Jungen, Christiane; Pape, Ulrike; Kraft, Axel; Warnke, Svenja; Lindner, Diana; Westermann, Dirk; Blankenberg, Stefan; Meyer, Christian; Hasenfuss, Gerd; Lehnart, Stephan E; Nikolaev, Viacheslav.

In: CIRC RES, Vol. 129, No. 1, 25.06.2021, p. 81-94.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Berisha, F, Götz, KR, Wegener, J, Brandenburg, S, Subramanian, H, Molina, C, Rüffer, A, Petersen, J, Bernhardt, A, Girdauskas, E, Jungen, C, Pape, U, Kraft, A, Warnke, S, Lindner, D, Westermann, D, Blankenberg, S, Meyer, C, Hasenfuss, G, Lehnart, SE & Nikolaev, V 2021, 'cAMP Imaging at Ryanodine Receptors Reveals β 2-Adrenoceptor Driven Arrhythmias', CIRC RES, vol. 129, no. 1, pp. 81-94. https://doi.org/10.1161/CIRCRESAHA.120.318234

APA

Berisha, F., Götz, K. R., Wegener, J., Brandenburg, S., Subramanian, H., Molina, C., Rüffer, A., Petersen, J., Bernhardt, A., Girdauskas, E., Jungen, C., Pape, U., Kraft, A., Warnke, S., Lindner, D., Westermann, D., Blankenberg, S., Meyer, C., Hasenfuss, G., ... Nikolaev, V. (2021). cAMP Imaging at Ryanodine Receptors Reveals β 2-Adrenoceptor Driven Arrhythmias. CIRC RES, 129(1), 81-94. https://doi.org/10.1161/CIRCRESAHA.120.318234

Vancouver

Berisha F, Götz KR, Wegener J, Brandenburg S, Subramanian H, Molina C et al. cAMP Imaging at Ryanodine Receptors Reveals β 2-Adrenoceptor Driven Arrhythmias. CIRC RES. 2021 Jun 25;129(1):81-94. https://doi.org/10.1161/CIRCRESAHA.120.318234

Bibtex

@article{0878f48097e447fd934f3d366e385035,
title = "cAMP Imaging at Ryanodine Receptors Reveals β 2-Adrenoceptor Driven Arrhythmias",
abstract = "Rationale:3′,5′-cAMP is a ubiquitous second messenger which, upon β-AR (β-adrenergic receptor) stimulation, acts in microdomains to regulate cardiac excitation-contraction coupling by activating phosphorylation of calcium handling proteins. One crucial microdomain is in vicinity of the cardiac RyR2 (ryanodine receptor type 2) which is associated with arrhythmogenic diastolic calcium leak from the sarcoplasmic reticulum often occurring in heart failure.Objective:We sought to establish a real-time live-cell imaging approach capable of directly visualizing cAMP in the vicinity of mouse and human RyR2 and to analyze its pathological changes in failing cardiomyocytes under β-AR stimulation.Methods and Results:We generated a novel targeted fluorescent biosensor Epac1 (exchange protein directly activated by cAMP 1)-JNC (junctin) for RyR2-associated cAMP and expressed it in transgenic mouse hearts as well in human ventricular myocytes using adenoviral gene transfer. In healthy cardiomyocytes, β1-AR but not β2-AR stimulation strongly increased local RyR2-associated cAMP levels. However, already in cardiac hypertrophy induced by aortic banding, there was a marked subcellular redistribution of PDEs (phosphodiesterases) 2, 3, and 4, which included a dramatic loss of the local pool of PDE4. This was also accompanied by measurable β2-AR/AMP signals in the vicinity of RyR2 in failing mouse and human myocytes, increased β2-AR–dependent RyR2 phosphorylation, sarcoplasmic reticulum calcium leak, and arrhythmia susceptibility.Conclusions:Our new imaging approach could visualize cAMP levels in the direct vicinity of cardiac RyR2. Unexpectedly, in mouse and human failing myocytes, it could uncover functionally relevant local arrhythmogenic β2-AR/cAMP signals which might be an interesting antiarrhythmic target for heart failure.",
author = "Filip Berisha and G{\"o}tz, {Konrad R.} and J. Wegener and S{\"o}ren Brandenburg and Hariharan Subramanian and Cristina Molina and Andr{\'e} R{\"u}ffer and Johannes Petersen and Alexander Bernhardt and Evaldas Girdauskas and Christiane Jungen and Ulrike Pape and Axel Kraft and Svenja Warnke and Diana Lindner and Dirk Westermann and Stefan Blankenberg and Christian Meyer and Gerd Hasenfuss and Lehnart, {Stephan E} and Viacheslav Nikolaev",
year = "2021",
month = jun,
day = "25",
doi = "10.1161/CIRCRESAHA.120.318234",
language = "English",
volume = "129",
pages = "81--94",
journal = "CIRC RES",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

RIS

TY - JOUR

T1 - cAMP Imaging at Ryanodine Receptors Reveals β 2-Adrenoceptor Driven Arrhythmias

AU - Berisha, Filip

AU - Götz, Konrad R.

AU - Wegener, J.

AU - Brandenburg, Sören

AU - Subramanian, Hariharan

AU - Molina, Cristina

AU - Rüffer, André

AU - Petersen, Johannes

AU - Bernhardt, Alexander

AU - Girdauskas, Evaldas

AU - Jungen, Christiane

AU - Pape, Ulrike

AU - Kraft, Axel

AU - Warnke, Svenja

AU - Lindner, Diana

AU - Westermann, Dirk

AU - Blankenberg, Stefan

AU - Meyer, Christian

AU - Hasenfuss, Gerd

AU - Lehnart, Stephan E

AU - Nikolaev, Viacheslav

PY - 2021/6/25

Y1 - 2021/6/25

N2 - Rationale:3′,5′-cAMP is a ubiquitous second messenger which, upon β-AR (β-adrenergic receptor) stimulation, acts in microdomains to regulate cardiac excitation-contraction coupling by activating phosphorylation of calcium handling proteins. One crucial microdomain is in vicinity of the cardiac RyR2 (ryanodine receptor type 2) which is associated with arrhythmogenic diastolic calcium leak from the sarcoplasmic reticulum often occurring in heart failure.Objective:We sought to establish a real-time live-cell imaging approach capable of directly visualizing cAMP in the vicinity of mouse and human RyR2 and to analyze its pathological changes in failing cardiomyocytes under β-AR stimulation.Methods and Results:We generated a novel targeted fluorescent biosensor Epac1 (exchange protein directly activated by cAMP 1)-JNC (junctin) for RyR2-associated cAMP and expressed it in transgenic mouse hearts as well in human ventricular myocytes using adenoviral gene transfer. In healthy cardiomyocytes, β1-AR but not β2-AR stimulation strongly increased local RyR2-associated cAMP levels. However, already in cardiac hypertrophy induced by aortic banding, there was a marked subcellular redistribution of PDEs (phosphodiesterases) 2, 3, and 4, which included a dramatic loss of the local pool of PDE4. This was also accompanied by measurable β2-AR/AMP signals in the vicinity of RyR2 in failing mouse and human myocytes, increased β2-AR–dependent RyR2 phosphorylation, sarcoplasmic reticulum calcium leak, and arrhythmia susceptibility.Conclusions:Our new imaging approach could visualize cAMP levels in the direct vicinity of cardiac RyR2. Unexpectedly, in mouse and human failing myocytes, it could uncover functionally relevant local arrhythmogenic β2-AR/cAMP signals which might be an interesting antiarrhythmic target for heart failure.

AB - Rationale:3′,5′-cAMP is a ubiquitous second messenger which, upon β-AR (β-adrenergic receptor) stimulation, acts in microdomains to regulate cardiac excitation-contraction coupling by activating phosphorylation of calcium handling proteins. One crucial microdomain is in vicinity of the cardiac RyR2 (ryanodine receptor type 2) which is associated with arrhythmogenic diastolic calcium leak from the sarcoplasmic reticulum often occurring in heart failure.Objective:We sought to establish a real-time live-cell imaging approach capable of directly visualizing cAMP in the vicinity of mouse and human RyR2 and to analyze its pathological changes in failing cardiomyocytes under β-AR stimulation.Methods and Results:We generated a novel targeted fluorescent biosensor Epac1 (exchange protein directly activated by cAMP 1)-JNC (junctin) for RyR2-associated cAMP and expressed it in transgenic mouse hearts as well in human ventricular myocytes using adenoviral gene transfer. In healthy cardiomyocytes, β1-AR but not β2-AR stimulation strongly increased local RyR2-associated cAMP levels. However, already in cardiac hypertrophy induced by aortic banding, there was a marked subcellular redistribution of PDEs (phosphodiesterases) 2, 3, and 4, which included a dramatic loss of the local pool of PDE4. This was also accompanied by measurable β2-AR/AMP signals in the vicinity of RyR2 in failing mouse and human myocytes, increased β2-AR–dependent RyR2 phosphorylation, sarcoplasmic reticulum calcium leak, and arrhythmia susceptibility.Conclusions:Our new imaging approach could visualize cAMP levels in the direct vicinity of cardiac RyR2. Unexpectedly, in mouse and human failing myocytes, it could uncover functionally relevant local arrhythmogenic β2-AR/cAMP signals which might be an interesting antiarrhythmic target for heart failure.

U2 - 10.1161/CIRCRESAHA.120.318234

DO - 10.1161/CIRCRESAHA.120.318234

M3 - SCORING: Journal article

VL - 129

SP - 81

EP - 94

JO - CIRC RES

JF - CIRC RES

SN - 0009-7330

IS - 1

ER -