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Gαq interactome in cell homeostasis and communication: impact on tissue architecture remodeling and endothelial dysfunction

21st national competition for scientific and technical research

Intercellular Dialogue and Interactome: Pathological Implications

Senior Researcher : Catalina Ribas Núñez

Research Centre or Institution : Fundación Severo Ochoa, CBM

Abstract

G protein-coupled receptors (GPCR) acting via Gq proteins are key for vascular homeostasis and are involved in pathologies related to endothelial dysfunction. Gαq activates its canonical effector PLCβ stimulating PKCs and mobilization of Ca2+. However, emerging evidence indicates the existence of alternative effectors involved in the physiological functions of Gαq. We have described a new effector region in Gαq able to interact with proteins that contain PB1 domains, such as PKCζ or p62. Importantly, we have recently identified an unforeseen role of Gαq as a core modulator of mTORC1 and macroautophagy (MA) via interaction of Gαq with the PB1 domain-containing protein p62, which play features of a Gαq effector. Given the important role of Gq-GPCR signaling in endothelial dysfunction and mechanosensing signaling, the emerging connections between endothelial autophagy, exosome release, inflammation and extracellular matrix remodeling, and our preliminary results using mouse models suggesting that this new Gαq effector region modulates endothelial function in response to inflammatory stimuli, the objective of this project is to delve deeper into the implication of Gαq networks in endothelial dysfunction, by exploring the connections between Gq pathways, caveolin, mechanical stretch and exosome secretion-autophagy interactions. 

We plan to investigate 1) the role of canonical and novel Gαq interactomes in the integrated modulation of autophagy processes, exosome trafficking, extracellular matrix remodeling and inflammation, and the identification of upstream stimulus and mechanisms involved; and 2) the implication of Gαq networks in endothelial dysfunction in vivo. The identification of new signaling pathways that relate Gαq to the crosstalk between different cell homeostasis and communication machineries will provide a better understanding of the impact of maladaptive Gq-coupled GPCR activation in pathological conditions and allow the design of targeted and more specific biased therapies.

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