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Involvement of biased agonism on trafficking and signaling of Angiotensin II AT1 receptor

Grant number: 13/01261-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2013
Effective date (End): October 31, 2017
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Claudio Miguel da Costa Neto
Grantee:Lucas Tabajara Parreiras e Silva
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
Associated scholarship(s):15/09131-6 - Bioengineering new BRET-based biosensors to analyze GPCR signal transduction from different intracellular compartments, BE.EP.PD

Abstract

G-protein coupled receptors (GPCRs) also known as seven transmembrane domains receptors (7TMRs) constitute the largest family of membrane receptors and are targets of about 50% of the drugs available on the market. It is now known that signaling of GPCRs is complex, since these receptors are able to activate various signaling pathways, in addition to different isoforms of protein G. It is well described that ²-arrestins are scaffold proteins that recruit various protein kinases during the internalization process, leading to the activation of various signaling pathways, such as the MAPKs, ERK1/2, among others. Furthermore, more recently it was described that different ligands can trigger different signaling pathways through the same receptor. This phenomenon is known as functional selectivity, or more biased agonism.Other important processes for the regulation of the functionality of membrane receptors are internalization, desensitization (degradation) and resensitization (recycling). These processes are dependent of the formation, traffic and fusion of vesicles, which in turn are regulated accurately by proteins called Rab GTPases. Some studies suggest a role for ²-arrestins in regulating the kinetics of the recycling process of GPCRs. However, so far no studies have been described with an assessment of the combined effect of activation of GPCRs by selective agonists and intracellular trafficking of these receptors, and the role of each isoform of ²-arrestin in this process.Thus, the aim of this project is to evaluate the intracellular trafficking pathways of angiotensin II AT1 receptor upon activation by its selective agonist, [Sar1-Ile4, 8] AngII (SII) using Rab GTPases as intracellular markers, and the role of ²- arrestins on recycling and degradation of the AT1 receptor. In addition, we will correlate the intracellular route embraced by this GPCR with the signaling pathways activated by it, using dominant negative forms of Rab GTPases.