Endothelin binds to receptors belonging to the family of G-protein-coupled receptors with an N-terminal extracellular domain that is suspected to be part of the binding site. We have synthesized different peptides of this N-terminal extracellular domain and analyzed the increase in calcium concentration ([Ca 2 + ] i ) induced by these peptides in the MEG-01 cell line and their influence on the ET-1 concentration-effect response. Nt(20-79) exhibited a partial agonistic effect on [Ca 2 + ] i and blunted the functional response of ET-1 in MEG-01 cells, but was not able to compete with radiolabeled ET-1 binding. The agonist effect was inhibited by the ET receptor antagonists PD142893 and BQ123, suggesting an interaction between Nt(20-79) and the ET A receptor at a site that could be different from the one of ET-1.