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 t o participate in certain neurodegenerative processes. However, the regulato ry effects of DA on glial cells have not been extensively studied. Using a rat C6 glioma cell line stably expressing recombinant D2L receptors, we hav e found that micromolar levels of DA stimulate mitogenesis and glial fibril lary acidic protein (GFAP) expression, both serving as parameters of reacti ve gliosis. This mitogenesis occurs about 29 h after exposure to DA and req uires 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-de pendent oxidase, or NAG, an anti-oxidant, effectively prevented DA-induced tyrosine phosphorylation and DNA synthesis. Preincubation of (+)-butaclamol , a D2 receptor antagonist, inhibits both DA-stimulated tyrosine phosphoryl ation and mitogenesis. DA at micromolar levels also stimulates GFAP express ion. This DA-regulated GFAP expression can be completely inhibited by SB203 580, a selective p38 MAPK inhibitor, but not influenced by (+)-butaclamol a nd genistein, a protein tyrosine kinase inhibitor. Thus, our data suggest t hat regulation of DNA synthesis and GFAP expression induced by DA is mediat ed by independent signaling pathways. The mitogenesis requires a D2-recepto r-mediated protein tyrosine kinase cascade, while GFAP expression needs a D 2-receptor-independent p38 MAPK activation. This observation may help to un derstand the processes of reactive gliosis in some dopaminergic-related neu rodegenerative diseases. (C) 1999 Elsevier Science B.V. All rights reserved .