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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.)

Angiotensin II Type 1 Receptor Tachyphylaxis Is Defined by Agonist Residence Time

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Duarte, Diego A. [1] ; Parreiras-e-Silva, Lucas T. [1] ; Oliveira, Eduardo B. [1] ; Bouvier, Michel [2] ; Costa-Neto, Claudio M. [1]
Total Authors: 5
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil
[2] Univ Montreal, IRIC, Dept Biochem & Mol Med, Montreal, PQ - Canada
Total Affiliations: 2
Document type: Journal article
Source: Hypertension; v. 79, n. 1, p. 115-125, JAN 2022.
Web of Science Citations: 0

Several GPCRs (G-protein-coupled receptors) have been reported to exhibit tachyphylaxis, which is an acute loss of functional receptor response after repeated stimuli with an agonist. GPCRs are important clinical targets for a wide range of disorders. Therefore, elucidation of the ligand features that contribute to receptor tachyphylaxis and signaling events underlying this phenomenon is important for drug discovery and development. In this study, we examined the role of ligand-binding kinetics in the tachyphylaxis of AT(1)R (angiotensin II type 1 receptor) using bioluminescence resonance energy transfer assays to monitor signaling events under both kinetic and equilibrium conditions. We investigated AT(1)R signal transduction and translocation promoted by the endogenous tachyphylactic agonist Ang II (angiotensin II) and its analogs, described previously for inducing reduced receptor tachyphylaxis. Estimation of binding kinetic parameters of the ligands revealed that the residence time of Ang II was higher than that of the analogs, resulting in more sustained G(q) protein activation and recruitment of beta-arrestin than that promoted by the analogs. Furthermore, we observed that Ang II led to more sustained internalization of the receptor, thereby retarding its recycling to the plasma membrane and preventing further receptor responses. These results show that the apparent lack of tachyphylaxis in the studied analogs resulted from their short residence time at the AT(1)R. In addition, our data highlight the relevance of complete characterization of novel GPCR drug candidates, taking into account their receptor binding kinetics as well. (AU)

FAPESP's process: 16/15914-6 - Assessing the microdomain localization-dependent role of GPCRs and effectors on signal transduction using Bioluminescence Resonance Energy Transfer (BRET)-based biosensors
Grantee:Diego Ângelo Duarte
Support Opportunities: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 18/13655-9 - Space-time characterization of G protein-coupled receptors (GPCRs) signal transduction through new bioluminescence resonance energy transfer (BRET)-based biosensors
Grantee:Diego Ângelo Duarte
Support Opportunities: Scholarships in Brazil - Post-Doctoral
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 Opportunities: Research Projects - Thematic Grants
FAPESP's process: 16/24120-3 - Study of non-canonical roles of G proteins as new signaling mechanisms with impact on discovery and development of new drugs
Grantee:Lucas Tabajara Parreiras e Silva
Support Opportunities: Research Grants - Young Investigators Grants
FAPESP's process: 14/09893-0 - Design and synthesis of novel AT1 receptor ligands: biochemical and pharmacological characterization in search of biased agonists (biased agonists)
Grantee:Diego Ângelo Duarte
Support Opportunities: Scholarships in Brazil - Doctorate