Cytodifferentiation enhances Erk activation induced by endothelin-1 in primary cultured astrocytes.
We have previously demonstrated that endothelin-1 (ET-1)-induced extracellular signal-regulated kinase (Erk) activity via the ETB receptor (EDNRB) is mediated through two independent pathways, a protein kinase C-dependent pathway and a pertussis toxin (PTX)-sensitive pathway, in astrocytes. In this study, we showed that the molar potency of ET-1 to induce Erk activation was two orders of magnitude higher in dibutyryl cAMP (DBcAMP)-treated astrocytes than in quiescent astrocytes. This DBcAMP-enhanced molar potency of ET-1 in Erk activation was selectively inhibited by pretreatment of astrocytes with PTX. The expression level of EDNRB in astrocytes was markedly upregulated by DBcAMP-induced cytodifferentiation. However, this up-regulation was simply attributed to the high expression of low-affinity sites. The molar potency of ET-1 to induce both stimulation of inositol trisphosphate production and activation of protein kinase C in DBcAMP-treated astrocytes was similar to that in quiescent astrocytes. On the contrary, the molar potency of ET-1 to induce accumulation of Ras-GTP was two orders of magnitude higher in DBcAMP-treated astrocytes than in quiescent astrocytes, which was consistent with the case of ET-1-induced Erk activation. Moreover, the ET-1-induced Ras activation was PTX sensitive. These results suggest that cytodifferentiation selectively enhances the PTXsensitive Ras/Erk pathway induced by ET-1 in astrocytes, and that cytodifferentiation-induced EDNRB up-regulation might not contribute to this selective potentiation of ET-1 signaling.
Asada
Sachie
S
Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Japan.
Takanami-Ohnishi
Yoko
Y
Zhou
Jing
J
Hama
Hiroshi
H
Fukamizu
Akiyoshi
A
Kimura
Sadao
S
Goto
Katsutoshi
K
Kasuya
Yoshitoshi
Y
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D044023:Receptor, Endothelin B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism
D019332:Endothelin-1; D004676:Myelin Basic Protein; D044023:Receptor, Endothelin B; D003994:Bucladesine; D015544:Inositol 1,4,5-Trisphosphate; D037342:Pertussis Toxin; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins