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

Carmine Morisco, David Zebrowski, Gianluigi Condorelli, Philip Tsichlis, Stephen F. Vatner, Junichi Sadoshima

Research output: Contribution to journalArticlepeer-review

Abstract

We examined the mechanism of atrial natriuretic factor (ANF) transcription by isoproterenol (ISO), an agonist for the β-adrenergic receptor (βAR), 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 Ca2+/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 GSK3β. Overexpression of GSK3β inhibited ANF transcription, which was reversed by ISO.ISO failed to reverse the inhibitory effect of GSK3β(S9A), an Akt-insensitive mutant. Kinase-inactive GSK3β 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 βAR-induced Akt activation and ANF transcription in cardiac myocytes. Furthermore, βAR-stimulated ANF transcription is predominantly mediated by activation of Akt and subsequent phosphorylation/inhibition of GSK3β.

Original languageEnglish
Pages (from-to)14466-14475
Number of pages10
JournalJournal of Biological Chemistry
Volume275
Issue number19
DOIs
Publication statusPublished - May 12 2000

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'The Akt-glycogen synthase kinase 3β pathway regulates transcription of atrial natriuretic factor induced by β-adrenergic receptor stimulation in cardiac myocytes'. Together they form a unique fingerprint.

Cite this