Endothelins are potent mitogens that stimulate extracellular signal-regulated kinases (ERK/MAP kinases) through their cognate G-protein-coupled receptors, ET A and ET B . To address the role of post-translational ET receptor modifications such as acylation on ERK activation and to identify relevant downstream effectors coupling the ET receptor to the ERK signaling cascades we have constructed a panel of palmitoylation-deficient ET receptor mutants with differential Ga protein binding capacity. Endothelin-1 stimulation of wild-type ET A or ET B induced a fivefold to sixfold increase in ERK in COS-7 and CHO cells whereas fulllength nonpalmitoylated ET A and ET B mutants failed to stimulate ERK. A truncated ET B lacking the C-terminal tail domain including putative phosphorylation and arrestin binding site(s) but retaining the critical palmitoylation site(s) was still able to fully stimulate ERK activation. Using mutated ET receptors with selective G-protein-coupling we found that endothelin-induced stimulation of Ga q , but not of