Control of cytoplasmic and nuclear protein kinase A by phosphodiesterases and phosphatases in cardiac myocytes

Zeineb Haj Slimane, Ibrahim Bedioune, Patrick Lechêne, Audrey Varin, Florence Lefebvre, Philippe Mateo, Valérie Domergue-Dupont, Matthias Dewenter, Wito Richter, Marco Conti, Ali El-Armouche, Jin Zhang, Rodolphe Fischmeister, Grégoire Vandecasteele

Research output: Contribution to journalArticle

Abstract

AimsThe cAMP-dependent protein kinase (PKA) mediates β-adrenoceptor (β-AR) regulation of cardiac contraction and gene expression. Whereas PKA activity is well characterized in various subcellular compartments of adult cardiomyocytes, its regulation in the nucleus remains largely unknown. The aim of the present study was to compare the modalities of PKA regulation in the cytoplasm and nucleus of cardiomyocytes.Methods and resultsCytoplasmic and nuclear cAMP and PKA activity were measured with targeted fluorescence resonance energy transfer probes in adult rat ventricular myocytes. β-AR stimulation with isoprenaline (Iso) led to fast cAMP elevation in both compartments, whereas PKA activity was fast in the cytoplasm but markedly slower in the nucleus. Iso was also more potent and efficient in activating cytoplasmic than nuclear PKA. Similar slow kinetics of nuclear PKA activation was observed upon adenylyl cyclase activation with L-858051 or phosphodiesterase (PDE) inhibition with 3-isobutyl-1-methylxantine. Consistently, pulse stimulation with Iso (15 s) maximally induced PKA and myosin-binding protein C phosphorylation in the cytoplasm, but marginally activated PKA and cAMP response element-binding protein phosphorylation in the nucleus. Inhibition of PDE4 or ablation of the Pde4d gene in mice prolonged cytoplasmic PKA activation and enhanced nuclear PKA responses. In the cytoplasm, phosphatase 1 (PP1) and 2A (PP2A) contributed to the termination of PKA responses, whereas only PP1 played a role in the nucleus.ConclusionOur study reveals a differential integration of cytoplasmic and nuclear PKA responses to β-AR stimulation in cardiac myocytes. This may have important implications in the physiological and pathological hypertrophic response to β-AR stimulation.

Original languageEnglish (US)
Pages (from-to)97-106
Number of pages10
JournalCardiovascular Research
Volume102
Issue number1
DOIs
StatePublished - 2014

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Phosphoric Diester Hydrolases
Nuclear Proteins
Cyclic AMP-Dependent Protein Kinases
Phosphoric Monoester Hydrolases
Cardiac Myocytes
Protein Kinases
Cytoplasm
Isoproterenol
L 858051
Phosphorylation
Cyclic AMP Response Element-Binding Protein
Fluorescence Resonance Energy Transfer
Adenylyl Cyclases
Adrenergic Receptors
Muscle Cells

Keywords

  • 3′-5′-cyclic nucleotide phosphodiesterases
  • cAMP-dependent protein kinase
  • Compartmentation
  • Nucleus
  • Ser/Thr protein phosphatases

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology
  • Medicine(all)

Cite this

Haj Slimane, Z., Bedioune, I., Lechêne, P., Varin, A., Lefebvre, F., Mateo, P., ... Vandecasteele, G. (2014). Control of cytoplasmic and nuclear protein kinase A by phosphodiesterases and phosphatases in cardiac myocytes. Cardiovascular Research, 102(1), 97-106. https://doi.org/10.1093/cvr/cvu029

Control of cytoplasmic and nuclear protein kinase A by phosphodiesterases and phosphatases in cardiac myocytes. / Haj Slimane, Zeineb; Bedioune, Ibrahim; Lechêne, Patrick; Varin, Audrey; Lefebvre, Florence; Mateo, Philippe; Domergue-Dupont, Valérie; Dewenter, Matthias; Richter, Wito; Conti, Marco; El-Armouche, Ali; Zhang, Jin; Fischmeister, Rodolphe; Vandecasteele, Grégoire.

In: Cardiovascular Research, Vol. 102, No. 1, 2014, p. 97-106.

Research output: Contribution to journalArticle

Haj Slimane, Z, Bedioune, I, Lechêne, P, Varin, A, Lefebvre, F, Mateo, P, Domergue-Dupont, V, Dewenter, M, Richter, W, Conti, M, El-Armouche, A, Zhang, J, Fischmeister, R & Vandecasteele, G 2014, 'Control of cytoplasmic and nuclear protein kinase A by phosphodiesterases and phosphatases in cardiac myocytes', Cardiovascular Research, vol. 102, no. 1, pp. 97-106. https://doi.org/10.1093/cvr/cvu029
Haj Slimane, Zeineb ; Bedioune, Ibrahim ; Lechêne, Patrick ; Varin, Audrey ; Lefebvre, Florence ; Mateo, Philippe ; Domergue-Dupont, Valérie ; Dewenter, Matthias ; Richter, Wito ; Conti, Marco ; El-Armouche, Ali ; Zhang, Jin ; Fischmeister, Rodolphe ; Vandecasteele, Grégoire. / Control of cytoplasmic and nuclear protein kinase A by phosphodiesterases and phosphatases in cardiac myocytes. In: Cardiovascular Research. 2014 ; Vol. 102, No. 1. pp. 97-106.
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AU - Haj Slimane, Zeineb

AU - Bedioune, Ibrahim

AU - Lechêne, Patrick

AU - Varin, Audrey

AU - Lefebvre, Florence

AU - Mateo, Philippe

AU - Domergue-Dupont, Valérie

AU - Dewenter, Matthias

AU - Richter, Wito

AU - Conti, Marco

AU - El-Armouche, Ali

AU - Zhang, Jin

AU - Fischmeister, Rodolphe

AU - Vandecasteele, Grégoire

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N2 - AimsThe cAMP-dependent protein kinase (PKA) mediates β-adrenoceptor (β-AR) regulation of cardiac contraction and gene expression. Whereas PKA activity is well characterized in various subcellular compartments of adult cardiomyocytes, its regulation in the nucleus remains largely unknown. The aim of the present study was to compare the modalities of PKA regulation in the cytoplasm and nucleus of cardiomyocytes.Methods and resultsCytoplasmic and nuclear cAMP and PKA activity were measured with targeted fluorescence resonance energy transfer probes in adult rat ventricular myocytes. β-AR stimulation with isoprenaline (Iso) led to fast cAMP elevation in both compartments, whereas PKA activity was fast in the cytoplasm but markedly slower in the nucleus. Iso was also more potent and efficient in activating cytoplasmic than nuclear PKA. Similar slow kinetics of nuclear PKA activation was observed upon adenylyl cyclase activation with L-858051 or phosphodiesterase (PDE) inhibition with 3-isobutyl-1-methylxantine. Consistently, pulse stimulation with Iso (15 s) maximally induced PKA and myosin-binding protein C phosphorylation in the cytoplasm, but marginally activated PKA and cAMP response element-binding protein phosphorylation in the nucleus. Inhibition of PDE4 or ablation of the Pde4d gene in mice prolonged cytoplasmic PKA activation and enhanced nuclear PKA responses. In the cytoplasm, phosphatase 1 (PP1) and 2A (PP2A) contributed to the termination of PKA responses, whereas only PP1 played a role in the nucleus.ConclusionOur study reveals a differential integration of cytoplasmic and nuclear PKA responses to β-AR stimulation in cardiac myocytes. This may have important implications in the physiological and pathological hypertrophic response to β-AR stimulation.

AB - AimsThe cAMP-dependent protein kinase (PKA) mediates β-adrenoceptor (β-AR) regulation of cardiac contraction and gene expression. Whereas PKA activity is well characterized in various subcellular compartments of adult cardiomyocytes, its regulation in the nucleus remains largely unknown. The aim of the present study was to compare the modalities of PKA regulation in the cytoplasm and nucleus of cardiomyocytes.Methods and resultsCytoplasmic and nuclear cAMP and PKA activity were measured with targeted fluorescence resonance energy transfer probes in adult rat ventricular myocytes. β-AR stimulation with isoprenaline (Iso) led to fast cAMP elevation in both compartments, whereas PKA activity was fast in the cytoplasm but markedly slower in the nucleus. Iso was also more potent and efficient in activating cytoplasmic than nuclear PKA. Similar slow kinetics of nuclear PKA activation was observed upon adenylyl cyclase activation with L-858051 or phosphodiesterase (PDE) inhibition with 3-isobutyl-1-methylxantine. Consistently, pulse stimulation with Iso (15 s) maximally induced PKA and myosin-binding protein C phosphorylation in the cytoplasm, but marginally activated PKA and cAMP response element-binding protein phosphorylation in the nucleus. Inhibition of PDE4 or ablation of the Pde4d gene in mice prolonged cytoplasmic PKA activation and enhanced nuclear PKA responses. In the cytoplasm, phosphatase 1 (PP1) and 2A (PP2A) contributed to the termination of PKA responses, whereas only PP1 played a role in the nucleus.ConclusionOur study reveals a differential integration of cytoplasmic and nuclear PKA responses to β-AR stimulation in cardiac myocytes. This may have important implications in the physiological and pathological hypertrophic response to β-AR stimulation.

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