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

Author(s)

Barros, Alexandre J. ^[1] ; Ito, Christian M. ^[1] ; Makino, Elaine N. ^[1] ; Cembranelli, Fernando A. M. ^[1] ; Moraes, Francisco C. ^[1] ; Souza, Sinval E. G. ^[1] ; Oliveira, Laerte ^[1] ; Shimuta, Suma I. ^[1] ; Nakaie, Clovis R. ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Biophys, Escola Paulista Med, BR-04023062 Sao Paulo - Brazil

• Document type: Journal article
• Source: Biological Chemistry; v. 390, n. 12, p. 1265-1270, DEC 2009.
• Web of Science Citations: 1

Abstract

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, 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. (AU)

• FAPESP's process: 07/56480-0 - Synthesis and studies of peptides and analogues involved principally in the renin-angiotensin and kallikrein-kinin system
• Grantee: clovis ryuichi nakaie
• Support Opportunities: Research Projects - Thematic Grants