Regulation of heme oxygenase-1 expression by dopamine in cultured C6 glioma and primary astrocytes.
Heme oxygenase-1 (HO-1) is an inducible enzyme involved in heme catabolism, tissue iron homeostasis and the cellular response to oxidative stress. Elevated HO-1 expression in astrocytes has been observed in association with abnormal iron deposition and increased oxidative stress in Parkinson's disease (PD). Since HO-1 could contribute to these aspects of PD pathobiology we have investigated its regulation in cultured astrocytes and C6 glioma cells. Here we report that dopamine is a potent inducer of HO-1. This induction is not mediated by a classical dopamine receptor and is not mimicked by a range of catecholamines and dopamine metabolites. When the time-course of HO-1 expression was compared between dopamine and hemin, the latter induced the gene immediately while the former did so with a lag. This suggested two distinct signal transduction pathways. However, cycloheximide blocked both hemin- and dopamine-induced HO-1 expression, suggesting that both pathways may involve proteins with short half-lives. Ascorbic acid blocked dopamine induction of HO-1 but had no effect on hemin-induced expression. This suggested that dopamine may signal upstream of the unstable protein by producing pro-oxidant metabolites or byproducts. Inhibition of monoamine oxidases A or B or catechol-O-methyl transferase did not block HO-1 induction by dopamine, indicating that these enzymes were not converting dopamine to an active metabolite. These results suggest that dopamine, released or secreted from affected neurons, may trigger HO-1 expression in neighboring astrocytes. HO-1 and its metabolites could then contribute to the oxidative stress and iron deposition associated with PD.
Schmidt
J
J
Section of Pediatric Critical Care, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105-2794, USA.
Mertz
K
K
Morgan
J I
JI
D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005910:Glioma / Q000201:enzymology* / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D008565:Membrane Proteins; D008996:Monoamine Oxidase Inhibitors; D012333:RNA, Messenger; D015102:3,4-Dihydroxyphenylacetic Acid; C067713:lactacystin; D012642:Selegiline; D006427:Hemin; D003513:Cycloheximide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D001205:Ascorbic Acid; C057726:OR486; D004298:Dopamine; D000111:Acetylcysteine