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

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)