RRC ID 43036
Author Fukuda T, Ishii K, Nanmoku T, Isobe K, Kawakami Y, Takekoshi K.
Title 5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside stimulates tyrosine hydroxylase activity and catecholamine secretion by activation of AMP-activated protein kinase in PC12 cells.
Journal J Neuroendocrinol
Abstract The activity of AMP-activated protein kinase (AMPK) is regulated by the metabolic and nutritional state of the cell. 5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) is transformed into riboside monophosphate (ZMP) via phosphorylation by adenosine kinase inside the cell and exerts it effect by stimulating AMPK. AICAR significantly induces an increase in AMPK activity in a dose- and time-dependent manner in the rat pheochromocytoma cell line PC12. In addition, compound C, an AMPK inhibitor, as well as 5'-amino-5'-dAdo, an adenosine kinase inhibitor, inhibits the AICAR-induced AMPK activity. AICAR significantly stimulates tyrosine hydroxylase (TH) (the rate-limiting enzyme in the biosynthesis of catecholamine) activity and the corresponding mRNA level, which closely matches with the TH protein level. In addition, AICAR provokes a rapid and long-lasting increase in the phosphorylation of TH at Ser19, Ser31 and Ser40. AICAR also markedly activates ERKs, JNK and p38. The MEK-1-inhibitor (PD-098059) causes a partial, but significant, inhibition of AICAR-induced TH enzyme activity by phosphorylation of Ser31 without affecting phosphorylation at the two other sites. By contrast, neither the JNK-inhibitor nor the p38-inhibitor affects TH enzyme activity and phosphorylation. Similarly, PD-098059 partially, but significantly, inhibits the AICAR-induced increase in the TH mRNA level. Furthermore, AICAR increases the level of cAMP in PC12 cells. The present study also shows that H89, a protein kinase A inhibitor, abolishes the AICAR-induced increase in the level of TH mRNA, as well as the corresponding enzyme activity and Ser40 phosphorylation. Finally, AICAR significantly increases dopamine secretion from PC12 cells. These findings indicate that AICAR activates catecholamine synthesis and secretion through AMPK activation in chromaffin cells.
Volume 19(8)
Pages 621-31
Published 2007-8-1
DOI 10.1111/j.1365-2826.2007.01570.x
PMID 17620104
MeSH AMP-Activated Protein Kinases Aminoimidazole Carboxamide / analogs & derivatives* Aminoimidazole Carboxamide / pharmacology Animals Catecholamines / metabolism* Chromaffin Cells / drug effects Chromaffin Cells / metabolism Cyclic AMP / metabolism Dopamine / metabolism Enzyme Activation / drug effects Extracellular Signal-Regulated MAP Kinases / metabolism Gene Expression Regulation, Enzymologic / drug effects Models, Biological Multienzyme Complexes / metabolism* Multienzyme Complexes / physiology PC12 Cells Phosphorylation / drug effects Protein Kinase C / metabolism Protein Serine-Threonine Kinases / metabolism* Protein Serine-Threonine Kinases / physiology Rats Ribonucleosides / pharmacology* Tyrosine 3-Monooxygenase / genetics Tyrosine 3-Monooxygenase / metabolism*
IF 2.886
Times Cited 16
Human and Animal Cells PC-12(RCB0009)