Endothelin-1 stimulates c-fos mRNA expression in C6 glioma cells via MAP kinase pathway

Exposure of C6 glioma cells to endothelin-1 (ET-1) caused dose-dependent (1 0(-11) M to 10(-7) M) increments in intracellular calcium concentration ([C a+C](i)) and c-fos mRNA expression (4.5-fold) that were abolished by the en dothelin(A) receptor antagonist, BQ610, and by inhibition of phospholipase C with U73111. ET-1 stimulated c-fos mRNA expression was also inhibited by protein kinase C inhibition (chelerythrine) and by the MAP kinase kinase in hibitor PD98059, but not by inhibitors of tyrosine kinases, protein kinase A type I or II, calmodulin kinase II, or calcium channel blockade. C6 cells treated with ET-1 demonstrated a significant increase in MAP kinase activi ty as evidenced by Western blotting. These results indicate a mechanism of long-term signaling by ET-1 involving an ET, receptor-mediated, phospholipa se Cp-linked pathway that is dependent on protein kinase C and MAP kinase a ctivation. (C) 1999 Elsevier Science Inc. All rights reserved.