Pharmacologic responses to endothelins (ETs) are mediated by two subtypes of G-protein-coupled receptors, termed ET(A) and ET(B). A chimeric receptor that has the transmembrane domains (TMDs) IV-VI with the adjacent loop regions from ET(B) embedded in the remaining regions from ET(A) exhibits specific bindings to the N-terminally truncated ET(B) agonists 125I- BQ3020 and 125I-IRL1620, to the same level as that of wild-type ET(B) receptor. Furthermore, the ET(A)-selective antagonist BQ123 competed for the binding of these ET(B)-selective radioligands to this chimeric receptor, with K(i) values similar to those determined by using wild-type ET(A) 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.
- 'Message-address' concept
- Chimeric human endothelin receptors
- Selective endothelin ligands
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine