Mutational analysis of the interaction of the N- and C-terminal ends of angiotensin II with the rat AT(1A) receptor

Mutational analysis of the interaction of the N- and C-terminal ends of angiotensin II with the rat AT(1A) receptor

Author Costa-Neto, Claudio M. Google Scholar
Mikakawa, Ayumi A. 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
Institution Universidade Federal de São Paulo (UNIFESP)
Univ Copenhagen
Abstract 1. the role of different residues of the rat AT(1A) receptor in the interaction with the N- and C-terminal ends of angiotensin II (AngII) was studied by determining ligand binding and production of inositol phosphates (IP) in COS-7 cells transiently expressing the following AT(1A) mutants: T88H, Y92H, G196I, G196W and D278E.2 G196W and G196I retained significant binding and IF-production properties, indicating that bulky substituents in position 196 did not affect the interaction of AngII's C-terminal carboxyl with Lys(199) located three residues below.3 Although the T88A mutation did not affect binding, the T88H mutant had greatly decreased affinity for AngII, suggesting that substitution of Thr(88) by His might hinder binding through an indirect effect.4 the Y92H mutation caused loss of affinity for AngII that was much less pronounced than that reported for Y92A, indicating that His in that position can fulfil part of the requirements for binding.5 Replacing Asp(278) by Glu caused a much smaller reduction in affinity than replacing it by Ala, indicating the importance of Asp's beta-carboxyl group for AngII binding.6 Mutations in residues Thr(88), Tyr(92) and Asp(278) greatly reduced affinity for AngII but not for Sar(1) Leu(8)-AngII, suggesting unfavourable interactions between these residues and AngII's aspartic acid side-chain or N-terminal amino group, which might account for the proposed role of the N-terminal amino group of AngII in the agonist-induced desensitization (tachyphylaxis) of smooth muscles.
Keywords angiotensin II
AT(1) receptor
site-directed mutagenesis
Language English
Date 2000-07-01
Published in British Journal of Pharmacology. Basingstoke: Nature Publishing Group, v. 130, n. 6, p. 1263-1268, 2000.
ISSN 0007-1188 (Sherpa/Romeo, impact factor)
Publisher Nature Publishing Group
Extent 1263-1268
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000088383500010

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