Dopamine stimulates redox-tyrosine kinase signaling and p38 MAPK in activation of astrocytic C6-D2L cells.
An increase in dopamine (DA) availability in rat brain has been suggested to participate in certain neurodegenerative processes. However, the regulatory effects of DA on glial cells have not been extensively studied. Using a rat C6 glioma cell line stably expressing recombinant D2L receptors, we have found that micromolar levels of DA stimulate mitogenesis and glial fibrillary acidic protein (GFAP) expression, both serving as parameters of reactive gliosis. This mitogenesis occurs about 29 h after exposure to DA and requires D2-receptor-mediated intracellular redox-tyrosine kinase activation. Either DA or quinpirole, a D2 receptor agonist, stimulates protein tyrosine phosphorylation. Application of either DPI, a potent inhibitor of NADPH-dependent oxidase, or NAC, an anti-oxidant, effectively prevented DA-induced tyrosine phosphorylation and DNA synthesis. Preincubation of (+)-butaclamol, a D2 receptor antagonist, inhibits both DA-stimulated tyrosine phosphorylation and mitogenesis. DA at micromolar levels also stimulates GFAP expression. This DA-regulated GFAP expression can be completely inhibited by SB203580, a selective p38 MAPK inhibitor, but not influenced by (+)-butaclamol and genistein, a protein tyrosine kinase inhibitor. Thus, our data suggest that regulation of DNA synthesis and GFAP expression induced by DA is mediated by independent signaling pathways. The mitogenesis requires a D2-receptor-mediated protein tyrosine kinase cascade, while GFAP expression needs a D2-receptor-independent p38 MAPK activation. This observation may help to understand the processes of reactive gliosis in some dopaminergic-related neurodegenerative diseases.
Luo
Y
Y
Molecular Physiology and Genetics Section, NIA, Baltimore, MD 21224, USA. luoyq@helix.nih.gov
Kokkonen
G C
GC
Hattori
A
A
Chrest
F J
FJ
Roth
G S
GS
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D004298:Dopamine / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D008934:Mitogens / Q000494:pharmacology; D008970:Molecular Weight; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases
D065127:Dopamine D2 Receptor Antagonists; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008934:Mitogens; D017448:Receptors, Dopamine D2; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D004298:Dopamine