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.
Sakamoto
A
A
Department of Pharmacology, Faculty of Medicine, Kyoto University, Japan.
Yanagisawa
M
M
Sakurai
T
T
Nakao
K
K
Toyo-oka
T
T
Yano
M
M
Masaki
T
T
D001667:Binding, Competitive / Q000187:drug effects; D002678:Chimera; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008566:Membranes / Q000378:metabolism; D008954:Models, Biological; D010456:Peptides, Cyclic / Q000378:metabolism; D017466:Receptors, Endothelin / Q000737:chemistry / Q000378:metabolism*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D008024:Ligands; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)