Characterization of the signal transduction pathways mediating noradrenaline-stimulated MAPK activation and c-fos expression in oligodendrocyte progenitors.
In examining the signaling transduction pathway of adrenoceptors in oligodendrocyte progenitors, we have found that stimulation of alpha(1)-adrenoceptors with norepinephrine (NE), in the presence of 3 microM propranolol, increased the activity of mitogen-activated protein kinases (MAPKs). This stimulation was concentration- and time-dependent, with maximal response after 10 min of exposure to 10 microM NE. Pertussis toxin (PTX) blocked NE-mediated MAPK activation, suggesting that alpha(1)-adrenoceptor activates MAPK through a PTX-sensitive G-protein. In the presence of U73122, an inhibitor of phospholipase C (PLC), MAPK activation was blocked. In oligodendrocyte progenitor cultures, chronic treatment with phorbol-12-myristate-13-acetate (PMA) down-regulated protein kinase C (PKC) and blocked NE-mediated MAPK activation. The response to NE was also significantly decreased by the PKC inhibitors H7 and bisindolylmaleimide GF109203X. Similarly, the effect of NE on MAPK activation was not observed in a calcium-free medium. Furthermore, attenuation of MAPK activity was observed when cultures were pretreated with LY294002 and wortmannin, inhibitors of phosphatidylinositol-3 kinase (PI3K). These results suggest that alpha(1)-adrenoceptor-mediated activation of MAPK involves a PTX-sensitive G-protein, PLC, PI3K, and 1,2-diacyl glycerol (DAG)-dependent PKC isozyme. Stimulation of oligodendrocyte progenitors with NE also resulted in an increase in c-fos expression, which was mediated by both alpha(1)- and beta-adrenoceptor and was calcium-, PKC-, and protein kinase A (PKA)-dependent. Interestingly, in the presence of PD 098059, a specific inhibitor of MAPK kinase (MEK), both MAPK activity and c-fos expression were blocked. This suggests that MAPK is implicated in the transmission of the signal from alpha(1)-adrenoceptor to c-fos gene expression.
Khorchid
A
A
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Larocca
J N
JN
Almazan
G
G
D000818:Animals; D018929:Cell Culture Techniques; D019204:GTP-Binding Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism* / Q000494:pharmacology; D009836:Oligodendroglia / Q000201:enzymology*; D037342:Pertussis Toxin; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism*; D012313:RNA / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000201:enzymology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D016760:Proto-Oncogene Proteins c-fos; D011941:Receptors, Adrenergic; D010566:Virulence Factors, Bordetella; D012313:RNA; D037342:Pertussis Toxin; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D009638:Norepinephrine