Project description
Unravelling GPCR complexes for better therapies
Cells rely on G protein coupled receptors (GPCRs) to sense and respond to their environment, influencing countless biological processes. Traditionally viewed as isolated units, recent evidence reveals that GPCRs assemble into complexes called heteromers, enhancing their signalling diversity. These heteromers, with their tissue-specific characteristics, offer promising targets for more precise and safer drugs. However, the molecular mechanisms behind heteromer assembly and function remain poorly understood, limiting progress. The ERC-funded SignalHet project aims to unravel these mysteries, focusing on the mGlu2-5HT2A heteromer, implicated in schizophrenia. By leveraging cutting-edge biophysics, cryo-electron microscopy, and fluorescence techniques, SignalHet will explore the role of lipids, map heteromer structures, and uncover how these complexes generate unique cellular responses.
Objective
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 cells capacity to respond to its environment. Thanks to their strong tissue-specificity, these complexes -termed heteromer- also form important targets for the development of new drugs with less side effects. Still, our understanding of the molecular mechanisms by which assembly of GPCRs in complexes transform their signaling properties remain extremely sparse. 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. This proposal is organised in three objectives:
1/ A too often over-looked component of a GPCR environment is the lipidic membrane it is inserted in. Using a multi-scale biophysics approach, I will characterise 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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences physical sciences optics microscopy
- natural sciences biological sciences biochemistry biomolecules lipids
- humanities arts modern and contemporary art cinematography
- natural sciences biological sciences biophysics
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2023-STG
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75794 PARIS
France
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