Factors regulating tachyphylaxis triggered by N-terminal-modified angiotensin II analogs

Binding of angiotensin II (DRVYIHPF, AngII) to its AT(1) receptor can trigger a process known as tachyphylaxis (loss of receptor response owing to repeated agonist stimulation). We propose a two-state binding model for tachyphylaxis where the N-terminal Asp(1) and Arg(2) residues of the peptide are...

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Bibliographic Details
Published in:	Biological chemistry Vol. 390; no. 12; p. 1265
Main Authors:	Barros, Alexandre J, Ito, Christian M, Makino, Elaine N, Cembranelli, Fernando A M, Moraes, Francisco C, Souza, Sinval E G, Oliveira, Laerte, Shimuta, Suma I, Nakaie, Clovis R
Format:	Journal Article
Language:	English
Published:	Germany 01-12-2009
Subjects:	Angiotensin II - analogs & derivatives Angiotensin II - pharmacology Animals Female Guinea Pigs Ileum - drug effects In Vitro Techniques Male Molecular Structure Receptor, Angiotensin, Type 1 - agonists Tachyphylaxis
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Summary:	Binding of angiotensin II (DRVYIHPF, AngII) to its AT(1) receptor can trigger a process known as tachyphylaxis (loss of receptor response owing to repeated agonist stimulation). We propose a two-state binding model for tachyphylaxis where the N-terminal Asp(1) and Arg(2) residues of the peptide are supposed to initially bind to the N-terminal segment (Arg(23)) and to the EC-3 loop (Asp(281)) of an AT(1) molecule, respectively (state 1). Sequentially, a disruption of the salt bond between the AngII Asp(1) beta-carboxyl function and the receptor Arg(23) can occur with release of the peptide N-terminal segment, favoring the binding of the Arg(2) residue to the EC-3 loop (Asp(178,281), state 2). In the present study, we expanded this investigation by assaying pharmacological properties of different AngII analogs in guinea-pig ileum bearing modifications at positions 1 and 2. Most of these peptides were weak agonists but many of them had the ability to induce tachyphylaxis. These findings support the two-state model for tachyphylaxis, but alternative mechanisms were revealed where state 1 was no longer needed, depending on the chemical structure of AngII residue 1. Otherwise, any modification of the wild type AngII Arg(2) residue was deleterious for the tachyphylaxis mechanism.
ISSN:	1437-4315
DOI:	10.1515/BC.2009.143