Characterization of the signal transduction pathways mediating noradrenaline-stimulated MAPK activation and c-fos expression in oligodendrocyte progenitors
A. Khorchid et al., Characterization of the signal transduction pathways mediating noradrenaline-stimulated MAPK activation and c-fos expression in oligodendrocyte progenitors, J NEUROSC R, 58(6), 1999, pp. 765-778
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.