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Signal transduction and allosteric modulation of nicotinic acetylcholine recepto...

Signal transduction and allosteric modulation of nicotinic acetylcholine receptors from ion channel electrophysiology to atomic 3D structures Nicotinic acetylcholine receptors (nAChRs) mediate neuronal synaptic transmission and modulation. They contribute to higher brain functions such as cognition and reward and are important drug targets. Recent studies have revealed... see more

31/12/2024

CNRS

2M€

Project Budget: 2M€

Project leader

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

PARTICIPATION DEPralty Sin fecha límite de participación.

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Financing granted El organismo H2020 notifico la concesión del proyecto The day 2024-12-31

ERC-2017-ADG: ERC Advanced Grant Scope:Objectives

I+D

Cerrada does 8 years

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characteristics of the participant

Este proyecto no cuenta con búsquedas de partenariado abiertas en este momento.

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No hay información privada compartida para este proyecto. Habla con el coordinador.

2 Participantes

CNRS

2.28M€ | Leader

ARIES COMPLEX AERONAUTICA

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Project duration: 77 months Date Start: 2018-07-18
End date: 2024-12-31

Project leader

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Project Budget 2M€

participation deadline Sin fecha límite de participación.

Project description Nicotinic acetylcholine receptors (nAChRs) mediate neuronal synaptic transmission and modulation. They contribute to higher brain functions such as cognition and reward and are important drug targets. Recent studies have revealed that these acetylcholine-gated ion channels display an unanticipated conformational plasticity, adopting multiple allosteric states that shape the time course of their electrophysiological response. To date, a single nAChR structure has been solved at high resolution, and our understanding of the conformational transitions remains so far elusive. To address this challenge, we propose to develop a top-down approach starting from the study of the conformational transitions of nAChRs functionally expressed in cells, and then dissecting the molecular mechanisms on purified proteins. In WP1, we will develop an innovative fluorescence quenching approach to follow the protein motions concomitant with channel opening at the cell membrane. In WP2, we will further exploit this technique on purified proteins, to study the role/requirement of lipids, and their pharmacological crosstalk with allosteric modulators acting at the transmembrane domain. In WP3, the gained knowledge will open original routes to solve 3D structures of nAChRs, in novel conformations and in complex with allosteric modulators. The research will be centered on the major brain nAChRs, primarily the homomeric α7 and also the heteromeric α4β2 nAChRs that are major physiological players and key potential therapeutic targets. This multidisciplinary project combines electrophysiology, fluorescence, pharmacology, membrane protein biochemistry and structural biology, together with in silico modeling, molecular dynamics and ligand docking. The results will provide fundamental insights into the allosteric mechanisms underlying both nAChR function and its modulation by allosteric modulators that hold promises in therapeutics.

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