Studying the Non-canonical Signaling of G Proteins: Opportunities for New Pharmacological Approaches

• Grant number: 23/15864-2
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2025
• End date: March 31, 2027
• 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 Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

G protein-coupled receptors (GPCRs) are the main membrane proteins involved in the signal transduction process. GPCRs have a typical structure of seven transmembrane alpha-helices and can be activated by a huge range of molecules with physiological relevance such as monoamines, peptides, neurotransmitters, hormones, among others, regulating virtually all vital processes in the body. Due to their ubiquitous distribution and their pleiotropic roles, GPCRs are targets for about 35% of drugs available on the market and are still the main targets for discovery and development of new 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 the classic location of GPCRs is the plasma membrane, this is where the activation of G proteins is mainly studied and better understood. However, recent studies suggest the movement of GPCRs and G proteins to different intracellular compartments, with activation mechanisms far beyond those known for these proteins. In this context, new roles of G proteins, called "non-canonical roles", were proposed making it essential to understand the molecular mechanisms and possible pathophysiological consequences of regulating the location and function of these proteins in different intracellular compartments.The project proposed here is innovative as it addresses current issues of pharmacological interest, with a focus on the non-canonical actions of G proteins, a field to which few research groups in Brazil are dedicated. In addition, this project will introduce new pharmacological tools for the study of GPCRs signaling mechanisms that are difficult to approach using standard methods. Further, it will lead to a better understanding of non-canonical G protein signaling and its involvement in the action of drugs and, therefore, to the development of new therapeutic strategies in the treatment of pathologies in which GPCRs are involved. (AU)