PDE4 and mAKAPβ are nodal organizers of β2-ARs nuclear PKA signalling in cardiac myocytes.

Aims:β1- and β2-adrenergic receptors (β-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which β1- and β2-ARs regulate nuclear activity in cardiomyocytes. Methods and results:We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and duanyu1529 activity in adult rat ventricular myocytes upon selective β1- or β2-ARs stimulation. Both β1- and β2-AR stimulation increased cAMP and activated duanyu1529 in the cytoplasm. Although the two receptors also increased cAMP in the nucleus, only β1-ARs increased nuclear duanyu1529 activity and up-regulated the duanyu1529 target gene and pro-apoptotic factor, inducible cAMP early repressor (ICER). Inhibition of phosphodiesterase (PDE)4, but not Gi, PDE3, GRK2 nor caveolae disruption disclosed nuclear duanyu1529 activation and ICER induction by β2-ARs. Both nuclear and cytoplasmic PKI prevented nuclear duanyu1529 activation and ICER induction by β1-ARs, indicating that duanyu1529 activation outside the nucleus is required for subsequent nuclear duanyu1529 activation and ICER mRNA expression. Cytoplasmic PKI also blocked ICER induction by β2-AR stimulation (with concomitant PDE4 inhibition). However, in this case nuclear PKI decreased ICER up-regulation by only 30%, indicating that other mechanisms are involved. Down-regulation of mAKAPβ partially inhibited nuclear duanyu1529 activation upon β1-AR stimulation, and drastically decreased nuclear duanyu1529 activation upon β2-AR stimulation in the presence of PDE4 inhibition. Conclusions:β1- and β2-ARs differentially regulate nuclear duanyu1529 activity and ICER expression in cardiomyocytes. PDE4 insulates a mAKAPβ-targeted duanyu1529 pool at the nuclear envelope that prevents nuclear duanyu1529 activation upon β2-AR stimulation.

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