The ligand-receptor interactions of the endothelin systems are mediated by distinct "message" and "address" domains.

Pharmacologic responses to endothelins (ETs) are mediated by two subtypes of G-protein-coupled receptors, termed ETA and ETB. A chimeric receptor that has the transmembrane domains (TMDs) IV-VI with the adjacent loop regions from ETB embedded in the remaining regions from ETA exhibits specific binding to the N-terminally truncated ETB agonists 125I-BQ3020 and 125I-IRL1620, to the same level as that of wild-type ETB receptor. Furthermore, the ETA-selective antagonist BQ123 competed for the binding of these ETB-selective radioligands to this chimeric receptor, with Ki values similar to those determined by using wild-type ETA receptor and 125I-ET-1. These findings indicated that the endothelin systems consist of two distinct parts, both on the ligand and receptor sides. The N-terminal loop structure of the agonists and the TMDs IV-VI with adjoining loops of the receptors determine the isopeptide/subtype selectivity. On the other hand, the C-terminal linear portion of the isopeptides and the TMDs I-III and VII plus adjacent loops of the receptors are probably involved in ligand-receptor binding itself. This scheme can be explained by the classic "message-address" concept proposed for a number of peptidergic ligand families.