Control of cytoplasmic and nuclear protein kinase A by phosphodiesterases and phosphatases in cardiac myocytes - Archive ouverte HAL Access content directly
Journal Articles Cardiovascular Research Year : 2014

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

Abstract

Aims The cAMP-dependent protein kinase (PKA) mediates β-adrenoceptors (β-ARs) 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 Cytoplasmic and nuclear cAMP and PKA activity were measured with targeted and results FRET probes in adult rat ventricular myocytes. β-AR stimulation with isoprenaline (Iso) led to fast cAMP elevation in both compartments, whereas PKA activity increased fast in the cytoplasm but markedly slower in the nucleus. Iso was also more potent and efficient to activate 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 IBMX. Consistently, pulse stimulation with Iso (15 s) maximally induced PKA and myosin-binding protein C phosphorylation in the cytoplasm, but marginally activated PKA and CREB 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. Conclusion Our 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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hal-02896355 , version 1 (10-07-2020)

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Zeineb Haj Slimane, Ibrahim Bedioune, Patrick Lechêne, Audrey Varin, Florence Lefebvre, et al.. Control of cytoplasmic and nuclear protein kinase A by phosphodiesterases and phosphatases in cardiac myocytes. Cardiovascular Research, 2014, 102 (1), pp.97-106. ⟨10.1093/cvr/cvu029⟩. ⟨hal-02896355⟩
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