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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Comparative analyses of downstream signal transduction targets modulated after activation of the AT(1) receptor by two beta-arrestin-biased agonists

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Author(s):
Santos, Geisa A. [1] ; Duarte, Diego A. [1] ; Parreiras-e-Silva, Lucas T. [1] ; Teixeira, Felipe R. [2, 1] ; Silva-Rochay, Rafael [3] ; Oliveira, Eduardo B. [1] ; Bouvier, Michel [4] ; Costa-Neto, Claudio M. [1, 5]
Total Authors: 8
Affiliation:
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto - Brazil
[2] Univ Fed Sao Carlos, Dept Genet & Evolut, BR-13560 Sao Carlos, SP - Brazil
[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cellular & Mol Biol, BR-14049900 Ribeirao Preto - Brazil
[4] Univ Montreal, Dept Biochem & Mol Med, Montreal, PQ - Canada
[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Ctr Integrat Syst Biol CISBi, BR-14049900 Ribeirao Preto - Brazil
Total Affiliations: 5
Document type: Journal article
Source: FRONTIERS IN PHARMACOLOGY; v. 6, JUL 1 2015.
Web of Science Citations: 12
Abstract

G protein-coupled receptors (GPCRs) are involved in essentially all physiological processes in mammals. The classical GPCR signal transduction mechanism occurs by coupling to G protein, but it has recently been demonstrated that interaction with beta-arrestins leads to activation of pathways that are independent of the G protein pathway. Also, it has been reported that some ligands can preferentially activate one of these signaling pathways; being therefore called biased agonists for G protein or beta-arrestin pathways. The angiotensin II (AngII) AT1 receptor is a prototype GPCR in the study of biased agonism due to the existence of well-known beta-arrestin-biased agonists, such as {[}Sar(1), Ile(4), Ile(8)]-AngII (SII), and {[}Sar(1), D-Ala(8)]-AngII (TRV027). The aim of this study was to comparatively analyze the two above mentioned beta-arrestin-biased agonists on downstream phosphorylation events and gene expression profiles. Our data reveal that activation of AT1 receptor by each ligand led to a diversity of activation profiles that is far broader than that expected from a simple dichotomy between G protein-dependent and beta-arrestin-dependent signaling. We observed clusters of activation profiles common to AngII, SII, and TRV027, as well as downstream effector activation that are unique to AngII, SII, or TRV027. Analyses of beta-arrestin conformational changes after AT1 receptor stimulation with SII or TRV027 suggests that the observed differences could account, at least partially, for the diversity of modulated targets observed. Our data reveal that, although the categorization G protein-dependent vs. beta-arrestin-dependent signaling can be of pharmacological relevance, broader analyses of signaling pathways and downstream targets are necessary to generate an accurate activation profile for a given ligand. This may bring relevant information for drug development, as it may allow more refined comparison of drugs with similar mechanism of action and effects, but with distinct side effects. (AU)

FAPESP's process: 12/20148-0 - Development of new ligands/drugs with selective agonism action (biased agonism) for receptors of the renin-angiotensin and kallikrein-kinin systems: new properties and new biotechnological applications
Grantee:Claudio Miguel da Costa Neto
Support type: Research Projects - Thematic Grants