We examined the mechanism of atrial natriuretic factor (ANF) transcription by isoproterenol (ISO), an agonist for the beta-adrenergic receptor (betaAR), in cardiac myocytes. ISO only modestly activated members of the mitogen-activated protein kinase family. ISO-induced ANF transcription was not affected by inhibition of mitogen-activated protein kinases, whereas it was significantly inhibited by KN93, an inhibitor of Ca(2+)/calmodulin-dependent kinase (CaM kinase II). Production of 3'-phosphorylated phosphatidylinositides (3 phosphoinositides) was also required for ISO-induced ANF transcription. ISO caused phosphorylation (Ser-473) and activation of Akt through CaM kinase II- and 3 phosphoinositides-dependent mechanisms. Constitutively active Akt increased myocyte surface area, total protein content, and ANF expression, whereas dominant negative Akt blocked ISO-stimulated ANF transcription. ISO caused Ser-9 phosphorylation and decreased activities of GSK3beta. Overexpression of GSK3beta inhibited ANF transcription, which was reversed by ISO. ISO failed to reverse the inhibitory effect of GSK3beta(S9A), an Akt-insensitive mutant. Kinase-inactive GSK3beta increased ANF transcription. Cyclosporin A partially inhibited ISO-stimulated ANF transcription, indicating that calcineurin only partially mediates ANF transcription. These results suggest that both CaM kinase II and 3 phosphoinositides mediate betaAR-induced Akt activation and ANF transcription in cardiac myocytes. Furthermore, betaAR-stimulated ANF transcription is predominantly mediated by activation of Akt and subsequent phosphorylation/inhibition of GSK3beta.

The Akt-glycogen synthase kinase 3beta pathway regulates transcription of atrial natriuretic factor induced by beta-adrenergic receptor stimulation in cardiac myocytes

Condorelli, G;
2000-01-01

Abstract

We examined the mechanism of atrial natriuretic factor (ANF) transcription by isoproterenol (ISO), an agonist for the beta-adrenergic receptor (betaAR), in cardiac myocytes. ISO only modestly activated members of the mitogen-activated protein kinase family. ISO-induced ANF transcription was not affected by inhibition of mitogen-activated protein kinases, whereas it was significantly inhibited by KN93, an inhibitor of Ca(2+)/calmodulin-dependent kinase (CaM kinase II). Production of 3'-phosphorylated phosphatidylinositides (3 phosphoinositides) was also required for ISO-induced ANF transcription. ISO caused phosphorylation (Ser-473) and activation of Akt through CaM kinase II- and 3 phosphoinositides-dependent mechanisms. Constitutively active Akt increased myocyte surface area, total protein content, and ANF expression, whereas dominant negative Akt blocked ISO-stimulated ANF transcription. ISO caused Ser-9 phosphorylation and decreased activities of GSK3beta. Overexpression of GSK3beta inhibited ANF transcription, which was reversed by ISO. ISO failed to reverse the inhibitory effect of GSK3beta(S9A), an Akt-insensitive mutant. Kinase-inactive GSK3beta increased ANF transcription. Cyclosporin A partially inhibited ISO-stimulated ANF transcription, indicating that calcineurin only partially mediates ANF transcription. These results suggest that both CaM kinase II and 3 phosphoinositides mediate betaAR-induced Akt activation and ANF transcription in cardiac myocytes. Furthermore, betaAR-stimulated ANF transcription is predominantly mediated by activation of Akt and subsequent phosphorylation/inhibition of GSK3beta.
Non-programmatic
Animals
Atrial Natriuretic Factor
Calcineurin
Calcium
Calcium-Calmodulin-Dependent Protein Kinases
Cardiomegaly
Glycogen Synthase Kinase 3
MAP Kinase Signaling System
Myocardium
Oncogene Protein v-akt
Phosphatidylinositol 3-Kinases
Phosphorylation
Rats
Rats, Wistar
Receptors, Adrenergic, beta
Retroviridae Proteins, Oncogenic
Gene Expression Regulation
Transcription, Genetic
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/70568
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