Study of non-canonical roles of G proteins as new signaling mechanisms with impact on discovery and development of new drugs

• Grant number: 16/24120-3
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: December 01, 2017
• End date: November 30, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Lucas Tabajara Parreiras e Silva
• Grantee: Lucas Tabajara Parreiras e Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 19/00378-0 - Production of intracellular compartiments specific markers for the study of GPCR and g protein trafficking by BRET technology, BP.IC; 18/00865-5 - Study of non-canonical roles of G proteins as new signaling mechanisms with impact on discovery and development of new drugs, BP.JP

Abstract

G-Protein Coupled Receptors (GPCRs) are the major membrane proteins involved in the signal transduction process. GPCRs have a typical structure of seven transmembrane alpha-helices and can be activated by a wide range of molecules of physiological relevance such as monoamines, peptides, neurotransmitters, hormones, among others, and regulate virtually all processes vital to the organism. Due to its ubiquitous distribution and their pleiotropic roles, GPCRs are targets for about 40% of all drugs on the market and are still the major targets for the discovery and development of drugs. As the name GPCR suggests, the mechanism of action of these receptors involves the activation of G proteins, which in turn have a heterotrimeric structure composed of ±, ² and ³ subunits, being responsible for the regulation and activation of different effectors. As GPCRs are located in the plasma membrane, activation of G proteins is mainly studied and better understood at this site, however, recent reports in the literature suggest actions of G proteins in different intracellular compartments and novel activation mechanisms for these proteins. These new roles of G proteins, called "non-canonical roles", including the molecular mechanisms and possible pathophysiological consequences of location and function of these proteins in different intracellular compartments are still unclear. We are convinced that the development of this project will not only bring significant results, but also help in the development of new tools and cutting-edge methodologies that will allow the understanding of the spatiotemporal regulation of GPCRs, G proteins, and other signaling effectors, with great potential also for use in research and development of new drugs. (AU)

Scientific publications

(4)

(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)

CORRE, MICHELLE F.; BALICO-SILVA, ANDRE L.; KISS, DORA J.; FERNANDES, GUSTAVO A. B.; MARASCHIN, JHONATAN C.; PARREIRAS-E-SILVA, LUCAS T.; VARELA, MARINA T.; SIMOES, SARAH C.; BOUVIER, MICHEL; KESERU, GYORGY M.; et al. Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H-3 and H(4 )receptors. Bioorganic & Medicinal Chemistry, v. 30, JAN 15 2021. (16/24120-3, 17/05441-6, 12/20148-0, 16/25028-3, 18/03918-2, 18/00153-5, 16/08920-0, 16/23139-2)

DUARTE, DIEGO A.; PARREIRAS-E-SILVA, LUCAS T.; OLIVEIRA, EDUARDO B.; BOUVIER, MICHEL; COSTA-NETO, CLAUDIO M.. Angiotensin II Type 1 Receptor Tachyphylaxis Is Defined by Agonist Residence Time. Hypertension, v. 79, n. 1, p. 115-125, JAN 2022. (16/15914-6, 18/13655-9, 12/20148-0, 16/24120-3, 14/09893-0)

SIMOES, SARAH C.; BALICO-SILVA, ANDRE L.; PARREIRAS-E-SILVA, LUCAS T.; BITENCOURT, ANDRE L. B.; BOUVIER, MICHEL; COSTA-NETO, CLAUDIO M.. Signal Transduction Profiling of Angiotensin II Type 1 Receptor With Mutations Associated to Atrial Fibrillation in Humans. FRONTIERS IN PHARMACOLOGY, v. 11, DEC 22 2020. (16/08920-0, 12/20148-0, 16/24120-3, 15/50086-4)

WRIGHT, SHANE C.; LUKASHEVA, VIKTORIYA; LE GOUILL, CHRISTIAN; KOBAYASHI, HIROYUKI; BRETON, BILLY; MAILHOT-LAROUCHE, SAMUEL; BLONDEL-TEPAZ, ELODIE; VIEIRA, NICHELLE ANTUNES; COSTA-NETO, CLAUDIO; HEROUX, MADELEINE; et al. BRET-based effector membrane translocation assay monitors GPCR-promoted and endocytosis-mediated Gq activation at early endosomes. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 118, n. 20, MAY 18 2021. (16/24120-3)