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 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.
Department of Biophysics, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo 04023-062, Brazil.
Alexandre J
AJ
Barros
Christian M
CM
Ito
Elaine N
EN
Makino
Fernando A M
FA
Cembranelli
Francisco C
FC
Moraes
Sinval E G
SE
Souza
Laerte
L
Oliveira
Suma I
SI
Shimuta
Clovis R
CR
Nakaie
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists; D013618:Tachyphylaxis
D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II