Interaction of a non-peptide agonist with angiotensin II AT(1) receptor mutants

Interaction of a non-peptide agonist with angiotensin II AT(1) receptor mutants

Autor Costa-Neto, Claudio Miguel Google Scholar
Miyakawa, Ayumi A. Google Scholar
Pesquero, João Bosco Autor UNIFESP Google Scholar
Oliveira, Laerte Google Scholar
Hjorth, Siv A. Google Scholar
Schwartz, Thue W. Google Scholar
Paiva, Antonio Cechelli de Mattos Autor UNIFESP Google Scholar
Instituição Universidade Federal de São Paulo (UNIFESP)
Univ Copenhagen
Resumo To identify residues of the rat AT(1A) angiotensin II receptor involved with signal transduction and binding of the non-peptide agonist L-162,313 (5,7-dimethyl-2-ethyl-3-[[4-[2(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazol[4,5,6]-pyridine) we have performed ligand binding and inositol phosphate turnover assays in COS-7 cells transiently transfected with the wild-type and mutant forms of the receptor. Mutant receptors bore modifications in the extracellular region: T88H, Y92H, G196I, G196W, and D278E. Compound L-162,313 displaced [I-125]-Sar(1),Leu(8)-AngII from the mutants G196I and G196W with IC50 values similar to that of the wild-type. the affinity was, however, slightly affected by the D278E mutation and more significantly by the T88H and Y92H mutations. in inositol phosphate turnover assays, the ability of L-162,313 to trigger the activation cascade was compared with that of angiotensin II. These assays showed that the G196W mutant reached a relative maximum activation exceeding that of the wild-type receptor; the efficacy was slightly reduced in the G196I mutant and further reduced in the T88H, Y92H, and D278E mutants. Our data suggest that residues of the extracellular domain of the AT(1) receptor are involved in the binding of the non-peptide ligand, or in a general receptor activation phenomenon that involves conformational modifications for a preferential binding of agonists or antagonists.
Assunto angiotensin
non-peptide agonist
Idioma Inglês
Data 2002-05-01
Publicado em Canadian Journal of Physiology and Pharmacology. Ottawa: Natl Research Council Canada, v. 80, n. 5, p. 413-417, 2002.
ISSN 0008-4212 (Sherpa/Romeo, fator de impacto)
Editor Natl Research Council Canada
Extensão 413-417
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000175428800008

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