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Development of biosensors for monitoring signaling in subcellular compartments: a powerful molecular tool for drug discovery

Grant number: 15/50086-4
Support type:Regular Research Grants
Duration: March 01, 2016 - February 28, 2018
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Claudio Miguel da Costa Neto
Grantee:Claudio Miguel da Costa Neto
Principal investigator abroad: Michel Bouvier
Institution abroad: Université de Montréal, Canada
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant: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, AP.TEM

Abstract

G protein-coupled receptors (GPCRs) constitute the largest family of signal transducer proteins in mammals and are considered a major target for drug discovery. After stimulation, GPCRs activate G proteins and then recruit β- arrestins, which more recently has been shown to lead to G protein-independent signaling that can persist even in the internalized endosomes. Recent advances in GPCR pharmacology led to the identification of ligands that preferentially activate one of these pathways that are known as “biased agonists". Moreover, although it is assumed that G protein signaling is halted upon GPCR internalization, very recent data suggest that G protein signaling may be also triggered by GPCRs localized at the endosomes and other intracellular compartments. These mechanisms may provide spatiotemporal regulation of signaling cascades with important consequences for normal and pathological responses and for the development of better drugs. In an effort to address these issues, this project aims to investigate the spafiotemporal regulation of this second round of activation and its importance for cell physiology. We also want to address if biased agonists can also influence G protein activation from intracellular compartments with possible functional relevance. For this purpose, we will construct new BRET-based biosensors cellular activation by GPCRs localized in distinct intracellular compartments. (AU)

Articles published in Agência FAPESP about the research grant
Biosensors make new approaches to drug discovery possible 

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
TEIXEIRA, LARISSA B.; PARREIRAS-E-SILVA, LUCAS T.; BRUDER-NASCIMENTO, THIAGO; DUARTE, DIEGO A.; SIMOES, SARAH C.; COSTA, RAFAEL M.; RODRIGUEZ, DEISY Y.; FERREIRA, PEDRO A. B.; SILVA, CARLOS A. A.; ABRAO, EMILIANA P.; OLIVEIRA, EDUARDO B.; BOUVIER, MICHEL; TOSTES, RITA C.; COSTA-NETO, CLAUDIO M. Ang-(1-7) is an endogenous beta-arrestin-biased agonist of the AT(1) receptor with protective action in cardiac hypertrophy. SCIENTIFIC REPORTS, v. 7, SEP 19 2017. Web of Science Citations: 14.
PARREIRAS-E-SILVA, LUCAS T.; VARGAS-PINILLA, PEDRO; DUARTE, DIEGO A.; LONGO, DANAE; ESPINOZA PARDO, GRACE VIOLETA; FINKLER, ANDREA DULOR; PAIXAO-CORTES, VANESSA RODRIGUES; PARE, PAMELA; ROVARIS, DIEGO L.; OLIVEIRA, EDUARDO B.; CACERES, RAFAEL ANDRADE; GONCALVES, GISLENE L.; BOUVIER, MICHEL; SALZANO, FRANCISCO M.; LUCION, ALDO B.; COSTA-NETO, CLAUDIO M.; BORTOLINI, MARIA CATIRA. Functional New World monkey oxytocin forms elicit an altered signaling profile and promotes parental care in rats. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 114, n. 34, p. 9044-9049, AUG 22 2017. Web of Science Citations: 10.
COSTA-NETO, CLAUDIO M.; PARREIRAS-E-SILVA, LUCAS T.; BOUVIER, MICHEL. A Pluridimensional View of Biased Agonism. MOLECULAR PHARMACOLOGY, v. 90, n. 5, p. 587-595, NOV 1 2016. Web of Science Citations: 29.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.
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