Section 9
Chapter 8,710

Functional domains of human endothelin receptor

Adachi, M.; Hashido, K.; Trzeciak, A.; Watanabe, T.; Furuichi, Y.; Miyamoto, C.

Journal of Cardiovascular Pharmacology 22(Suppl): S121-S124


ISSN/ISBN: 0160-2446
PMID: 7509921
DOI: 10.1097/00005344-199322008-00033
Accession: 008709434

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The ligand binding site to the ET-A receptor was investigated by substitution of each 5-amino acid sequence located in the second extracellular (B) region of the ET-A receptor with the cognate sequences of the beta-2-adrenergic receptor. A 5-amino acid sequence (140-KLLAG-144) in the B-loop region was implicated as the most important element required for ligand binding. In addition, both the third and the fourth extracellular regions (C- and D-loops), including the flanking transmembrane regions, were found to play an important- role in ligand selection. As for the biological significance of the intracellular regions of the ET-A receptor, we have found that the C-terminal 8-amino acid residues located in close proximity to the seventh transmembrane region and the C-terminal 16-amino acid residues in the third intracellular loop are important for the binding of ET-1. Therefore, the intracellular third loop and C-terminal domains seem to contribute to the three-dimensional structure of the ligand binding site located in the extracellular domains. The same lines of experiment showed that the ET-A receptor requires gt 13 amino acid residues at the proximal cytoplasmic tail and 10 amino acid residues in the C-terminal region of the third intracellular loop to induce an ET-1-dependent increase in (Ca-2+)-i. Both regions are possibly involved in the interaction with G-protein.

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