Signal transduction and allosteric modulation of nicotinic acetylcholine receptors: from ion channel electrophysiology to atomic 3D structures

Projektinformationen

DYNACOTINE

ID Finanzhilfevereinbarung: 788974

DOI 10.3030/788974

EK-Unterschriftsdatum 18 Juli 2018

Startdatum 1 Januar 2019

Enddatum 31 Dezember 2024

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten € 2 282 105,00

EU-Beitrag € 2 282 105,00

Koordiniert durch

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Ziel

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.

Wissenschaftliches Gebiet

• natural sciences › biological sciences › biochemistry › biomolecules › proteins
• natural sciences › biological sciences › biochemistry › biomolecules › lipids
• medical and health sciences › basic medicine › pharmacology and pharmacy
• natural sciences › biological sciences › molecular biology › structural biology

Programm/Programme

• H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme

Thema/Themen

• ERC-2017-ADG - ERC Advanced Grant

Aufforderung zur Vorschlagseinreichung

ERC-2017-ADG

Finanzierungsplan

ERC-ADG - Advanced Grant

Gastgebende Einrichtung

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS

• Netto-EU-Beitrag: € 2 282 105,00
• Adresse: RUE MICHEL ANGE 3 ; 75794 Paris ; Frankreich
• Region: Ile-de-France › Ile-de-France › Paris
• Aktivitätstyp: Research Organisations
• Gesamtkosten: € 2 282 105,00

Begünstigte (1)

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS

Frankreich

• Netto-EU-Beitrag: € 2 282 105,00
• Adresse: RUE MICHEL ANGE 3 ; 75794 Paris
• Region: Ile-de-France › Ile-de-France › Paris
• Aktivitätstyp: Research Organisations
• Gesamtkosten: € 2 282 105,00