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Bioengineering new BRET-based biosensors to analyze GPCR signal transduction from different intracellular compartments

Grant number: 15/09131-6
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): June 10, 2015
Effective date (End): June 09, 2016
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Claudio Miguel da Costa Neto
Grantee:Lucas Tabajara Parreiras e Silva
Supervisor abroad: Michel Bouvier
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : Université de Montréal, Canada  
Associated to the scholarship:13/01261-2 - Involvement of biased agonism on trafficking and signaling of Angiotensin II AT1 receptor, BP.PD

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 ²-arrestins, which lead to disruption of G protein signaling and initiation of the internalization process. Although b-arrestin was first discovered for its role in interrupting G protein-mediated signaling it is now clear that the GPCR/²-arrestin complex can also lead to G protein-independent signaling and 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. However, very few tools are available to address that. In an effort to address these issues, the general aim of this study is to investigate the spatiotemporal regulation of this second round of G protein 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 to evaluate G protein activation by GPCRs localized in distinct intracellular compartments. (AU)