PhD in GPCRs biochemistry and structural biology (M/F)

Job Description

Thesis Subject

GPCRs are crucial for synaptic transmission and the regulation of various brain functions, such as plasticity, memory, and mood. Their dysfunction is linked to neuropsychiatric disorders, notably schizophrenia, a condition characterized by disruptions in glutamatergic and serotonergic pathways. The complex formed by the mGlu2 glutamate receptor and the 5-HT2A serotonin receptor is implicated in the psychotic symptoms of schizophrenia, making it a promising target for new treatments. Concurrently, membrane lipid abnormalities have been observed in patients with schizophrenia, suggesting a link between these anomalies and the pathology. However, the molecular mechanisms by which lipids modulate the formation, stability, and activity of GPCR heteromers remain poorly understood. This PhD project lies at the interface of neuroscience and structural biology; it aims to elucidate the molecular mechanisms by which membrane lipids regulate the structure and function of G protein-coupled receptor (GPCR) heteromers, focusing specifically on the mGlu2-5HT2A complex, a major therapeutic target for schizophrenia.
The goal of the thesis is to understand, at the molecular level, how GPCR heteromers modulate one another and the role lipids play in this modulation, using structural biology approaches and cryo-EM.
Specifically, this project will combine structural biology, biochemistry, and pharmacology to: (1) produce and purify the mGlu2-5HT2A heteromer in native lipid environments (HEK293/insect cells, nanodiscs); (2) resolve its 3D structure using cryo-EM to visualize interaction sites and functional modulation within the complex; (3) investigate the impact of lipids on heteromer signaling using HTRF/FRET assays.
This work will rely on state-of-the-art platforms (cryo-EM, HTRF) and international collaborations (Barcelona, ​​Montpellier). The results could lead to major advances in the understanding of schizophrenia and the development of treatments targeting lipid-GPCR interactions.

Your Work Environment

This project lies at the intersection of neuroscience and structural biology. It investigates the molecular mechanisms governing the activation and regulation of novel therapeutic targets for schizophrenia: Class C–Class A GPCR heteromers. A component of the project involves technological development, specifically for visualizing the structures of dynamic complex assemblies within native membranes.
G protein-coupled receptors (GPCRs) constitute a large family of receptors (comprising over 800 genes in humans). The laboratory focuses particularly on GPCRs found in the central nervous system, where they are involved in various functions ranging from synaptic plasticity to memory and addiction. Consequently, they represent significant pharmacological targets.
While GPCRs primarily function as individual units (monomers or obligate dimers), they can also assemble into larger complexes known as heteromers (1). We are particularly interested in heteromers formed between Class C and Class A GPCRs, specifically the heteromer composed of the metabotropic glutamate receptor mGlu2 and the serotonin receptor 5-HT2A (2). These complexes exhibit unique biochemical and pharmacological properties that differ from those of their constituent protomers (3–4). For instance, studies comparing healthy individuals with patients suffering from schizophrenia have shown that functional modulation within the mGlu2-5-HT2A heteromer is essential for maintaining a non-psychotic state (2).
Furthermore, numerous studies highlight the presence of lipid abnormalities in psychiatric disorders, particularly schizophrenia (5). However, the molecular mechanisms by which membrane lipids regulate the function of these GPCR complexes remain poorly understood. Thus, although they represent promising new pharmacological targets - particularly for schizophrenia, where the need for new treatments is urgent - the factors governing interactions within heteromers, as well as their precise role in health and disease, remain poorly understood.

1 : Ferré, S. et al. Building a new conceptual framework for receptor heteromers. Nature Chemical Biology 2009 5:3 5, 131–134 (2009).
2 : González-Maeso, J. et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452, 93–97 (2008).
3 : Fribourg, M. et al. Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychoticdrugs. Cell 147, 1011–1023 (2011).
4 : Gai, S., Lin, L., Meng, J. et al. Allosteric activation of the glutamate receptor mGlu2 by the serotonin receptor 5-HT2A. Nat Commun(2026).
5 : Tessier, C., Sweers, K., Frajerman, A. et al. Membrane lipidomics in schizophrenia patients: a correlational study with clinical and cognitive manifestations. Transl Psychiatry 6, e906 (2016).

Constraints and risks

NA

Compensation and benefits

Compensation

2300 € gross monthly

Annual leave and RTT

44 jours

Remote Working practice and compensation

Pratique et indemnisation du TT

Transport

Prise en charge à 75% du coût et forfait mobilité durable jusqu’à 300€

About the offer

About the CNRS

The CNRS is a major player in fundamental research on a global scale. The CNRS is the only French organization active in all scientific fields. Its unique position as a multi-specialist allows it to bring together different disciplines to address the most important challenges of the contemporary world, in connection with the actors of change.

CNRS

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