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 oligode ndrocyte progenitors, we have found that stimulation of alpha(1)-adrenocept ors,vith norepinephrine (NE), in the presence of 3 mu M propranolol, increa sed the activity of mitogen-activated protein kinases (MAPKs). This stimula tion was concentration- and time-dependent, with maximal response after 10 min of exposure to 10 mu M NE. Pertussis toxin (PTX) blocked NE-mediated MA PK activation, suggesting that al-adrenoceptor activates MARK through a PTX -sensitive G-protein. In the presence of U73122, an inhibitor of phospholip ase C (PLC), MAPK activation was blocked. In oligodendrocyte progenitor cul tures, chronic treatment with phorbol-12-myristate-13-acetate (PMA) down-re gulated protein kinase C (PKC) and blocked NE-mediated MAPK activation. The response to NE was also significantly decreased by the PKC inhibitors H7 a nd bisindolylmaleimide GF109203X. Similarly the effect of NE on MAPK activa tion was not observed in a calcium-free medium. Furthermore, attenuation of MARK activity was observed when cultures were pretreated with LY294002 and wortmannin, inhibitors of phosphatidylinositol-3 kinase (PI3K). These resu lts suggest that alpha(1)-adrenoceptor-mediated activation of MARK involves a PTX-sensitive G-protein, PLC, PI3K, and 1,2-diacyl glycerol (DAG)-depend ent PKC isozyme. Stimulation of oligodendrocyte progenitors with NE also re sulted 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 (PK A)-dependent. Interestingly, in the presence of PD 098059, a specific inhib itor of MAPK kinase (MEK), both MARK activity and c-fos expression were blo cked. This suggests that MAPK is implicated in the transmission of the sign al from alpha(1)-adrenoceptor to c-fos gene expression. J. Neurosci. Res. 5 8:765-778, 1999. (C) 1999 Wiley-Liss, Inc.