Coupling of endothelin receptors to the ERK/MAP kinase pathway

摘要: Endothelins are potent mitogens that stimulate extracellular signal-regulated kinases (ERK/MAP kinases) through their cognate G-protein-coupled receptors, ETA and ETB. To address the role of post-translational ET receptor modifications such as acylation on ERK activation to identify relevant downstream effectors coupling signaling cascades we have constructed a panel palmitoylation-deficient mutants with differential Gα protein binding capacity. Endothelin-1 stimulation wild-type or ETB induced fivefold sixfold increase in COS-7 CHO cells whereas full-length nonpalmitoylated failed ERK. A truncated lacking C-terminal tail domain including putative phosphorylation arrestin site(s) but retaining critical palmitoylation was still able fully activation. Using mutated receptors selective G-protein-coupling found endothelin-induced Gαq, not Gαi Gαs, is essential for endothelin-mediated Inhibition C epidermal growth factor kinase prevent ETA- ETB-mediated blockage phospholipase C-β completely abrogated endothelin-promoted recombinant native C6 cells. Complex formation Ca2+ inhibition Src family tyrosine prevented ET-1-induced ERK-2 C6-cells. Our results indicate ERK/MAPK criticially depends Gαq/phospholipase C-β/Ca2+/Src cascade necessary efficient pathway.