TY - JOUR
T1 - The Akt-glycogen synthase kinase 3β pathway regulates transcription of atrial natriuretic factor induced by β-adrenergic receptor stimulation in cardiac myocytes
AU - Morisco, Carmine
AU - Zebrowski, David
AU - Condorelli, Gianluigi
AU - Tsichlis, Philip
AU - Vatner, Stephen F.
AU - Sadoshima, Junichi
PY - 2000/5/12
Y1 - 2000/5/12
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.275.19.14466
DO - 10.1074/jbc.275.19.14466
M3 - Article
C2 - 10799529
AN - SCOPUS:0034640299
VL - 275
SP - 14466
EP - 14475
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 19
ER -