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

Abstract

AbstractBinding of angiotensin II (DRVYIHPF, AngII) to its AT1receptor 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 Asp1and Arg2residues of the peptide are supposed to initially bind to the N-terminal segment (Arg23) and to the EC-3 loop (Asp281) of an AT1molecule, respectively (state 1). Sequentially, a disruption of the salt bond between the AngII Asp1β-carboxyl function and the receptor Arg23can occur with release of the peptide N-terminal segment, favoring the binding of the Arg2residue to the EC-3 loop (Asp178,281, 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 Arg2residue was deleterious for the tachyphylaxis mechanism.