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Submitted on April 20, 2005
Accepted on August 31, 2005
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama City, 700-8558, Japan
* To whom correspondence should be addressed. E-mail: fumiotsu{at}md.okayama-u.ac.jp.
We here report a new physiological system that governs catecholamine synthesis involving bone morphogenetic proteins (BMPs) and activin in the rat pheochromocytoma cell line, PC12. BMP type I receptors, including activin receptor-like kinase (ALK)-2 (also referred to as ActRIA) and ALK-3 (BMPRIA), both type II receptors, ActRII and BMPRII, as well as the ligands BMP-2, -4, -7 and inhibin/activin subunits were expressed in PC12 cells. PC12 cells predominantly secrete dopamine while noradrenaline and adrenaline production is negligible. BMP-2, -4, -6, -7 and activin A each suppressed dopamine and cAMP synthesis in a dose-dependent fashion. The BMP ligands also decreased 3,4-dihydroxyphenylalanine decarboxylase (DDC) mRNA expression whereas activin suppressed tyrosine hydroxylase (TH) expression. BMPs induced both Smad1/5/8 phosphorylation and Tlx2-Luc activation while activin stimulated 3TP-Luc activity and p38 mitogen-activated protein kinase phosphorylation. Extracellular signal-regulated kinase signaling was not affected by BMPs or activin. Dexamethasone enhanced catecholamine synthesis accompanying increases in TH and DDC transcription without cAMP accumulation. In the presence of dexamethasone, BMPs and activin failed to reduce dopamine as well as cAMP production. In addition, dexamethasone also modulated mitotic suppression of PC12 induced by BMPs in a ligand-dependent manner. Furthermore, intracellular BMP signaling was markedly suppressed by dexamethasone treatment and the expression of ALK-2, ALK-3 and BMPRII was significantly inhibited by dexamethasone. Collectively, the endogenous BMP/activin system plays a key role in regulation of catecholamine production. Controlling activity of the BMP system may be critical for glucocorticoid-induced catecholamine synthesis by adrenomedullar cells.
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