Molecular mechanisms of GPCR heteromers signaling

Introduction

G Protein Coupled Receptors (GPCRs) are key mediators of how cells sense and react to their outside environment. Traditionally, these receptors have been thought to function as individual units at the cell surface. Over the past decade, new evidence has shown they can assemble in larger complexes to form new signaling entities and vastly expand a cell’s capacity to respond to its environment.

Importance of Heteromers

Thanks to their strong tissue-specificity, these complexes - termed heteromers - also form important targets for the development of new drugs with fewer side effects. Still, our understanding of the molecular mechanisms by which the assembly of GPCRs in complexes transforms their signaling properties remains extremely sparse.

Research Focus

My proposal investigates how heteromers interact and integrate changes in their environments to generate unique cellular responses. I focus my research on the mGlu2-5HT2A heteromer, as its existence has been demonstrated in humans and is involved in schizophrenia, a debilitating condition that urgently requires new treatments.

Objectives

This proposal is organized into three objectives:

1. A too often overlooked component of a GPCR environment is the lipidic membrane it is inserted in. Using a multi-scale biophysics approach, I will characterize the essential role lipids play in the assembly and function of heteromers, but also how receptors themselves change the membrane they are inserted in to transmit information.

2. I will use cryo-electron microscopy to solve the first structure of a heteromer, bound to its signaling partners, G proteins. I will go even further and develop cutting-edge EM tools to resolve a high-resolution movie of a GPCR heteromer signaling cascade, from receptor assembly to G protein activation.

3. Finally, using single particle cryoEM and fluorescence, I will investigate how heteromers recruit other partners which in turn modify receptors to form these new signaling units.