Orthovanadate Stimulates cAMP Phosphodiesterase 3 Activity in Isolated Rat Hepatocytes through Mitogen-Activated Protein Kinase Activation Dependent on cAMP-Dependent Protein Kinase

Orthovanadate (vanadate) as well as insulin stimulated phosphodiesterase 3 (PDE3) in the particulate fraction of rat hepatocytes. The vanadate-induced activations of PDE3 and mitogen-activated protein kinase (MAPK) were inhibited by H-89 and PD98059, suggesting that the MAPK activation via cAMP-depe...

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Published in:	Biological & Pharmaceutical Bulletin Vol. 27; no. 6; pp. 789 - 796
Main Authors:	Watanabe, Tomoyasu, Satoo, Hirofumi, Kohara, Kazuhisa, Takami, Reiko, Motoyashiki, Toshio, Morita, Tetsuo, Ueki, Hiroshi
Format:	Journal Article
Language:	English
Published:	Japan The Pharmaceutical Society of Japan 01-06-2004 Pharmaceutical Society of Japan Japan Science and Technology Agency
Subjects:	3',5'-Cyclic-AMP Phosphodiesterases - metabolism Animals cAMP-dependent protein kinase Cells, Cultured Cyclic AMP-Dependent Protein Kinases - metabolism Cyclic Nucleotide Phosphodiesterases, Type 3 Dose-Response Relationship, Drug Enzyme Activation - drug effects Enzyme Activation - physiology hepatocyte Hepatocytes - drug effects Hepatocytes - enzymology insulin Insulin - pharmacology Male mitogen-activated protein kinase Mitogen-Activated Protein Kinases - metabolism orthovanadate phosphodiesterase 3 Rats Rats, Wistar Vanadates - pharmacology
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Summary:	Orthovanadate (vanadate) as well as insulin stimulated phosphodiesterase 3 (PDE3) in the particulate fraction of rat hepatocytes. The vanadate-induced activations of PDE3 and mitogen-activated protein kinase (MAPK) were inhibited by H-89 and PD98059, suggesting that the MAPK activation via cAMP-dependent protein kinase (PKA) and MAPK kinase is involved in the vanadate action. On the other hand, the insulin-induced activations of PDE3 and Akt were inhibited by wortmannin, suggesting involvement of the Akt activation via phosphatidylinositol 3-kinase (PI3K) in the insulin action. The vanadate-induced activations of PKA and PDE3 were inhibited in part by propranolol or genistein, suggesting that vanadate may exert its actions via dual signaling pathways of β-adrenergic receptors and receptor tyrosine kinases of growth factors. Vanadate, in contrast to insulin, did not promote the phosphorylation of insulin receptor substrate-1. The vanadate-induced increase in the phosphorylation of a main isoform of MAPKs, p44 protein, was detected by immunoblotting migration patterns of SDS-PAGE. A partially purified PDE3 activity was increased by addition of MAPK or Akt to the reaction mixture, suggesting that MAPK as well as Akt acts upstream of PDE3. The activation of PDE3 by insulin was independent of a transient increase in the MAPK activity, probably due to the dephosphorylated inactivation mediated by the induced activation of MAPK phosphatases (MKPs). Vanadate did not affect the MKP activity. These results indicate that vanadate stimulates the particulate PDE3 activity by activating mainly p44 MAPK via a PKA-dependent process, and that it differs from insulin with regard to a phosphorylation cascade of PDE3 activation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0918-6158 1347-5215
DOI:	10.1248/bpb.27.789