Structure of a Human GABA(A) Receptor Complex

Projektinformationen

GABAARComp

ID Finanzhilfevereinbarung: 897707

DOI

10.3030/897707

Projekt abgeschlossen

EK-Unterschriftsdatum 23 März 2020

Startdatum 1 September 2021

Enddatum 31 August 2023

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 212 933,76

EU-Beitrag

€ 212 933,76

Koordiniert durch

UNITED KINGDOM RESEARCH AND INNOVATION
United Kingdom

Periodic Reporting for period 1 - GABAARComp (Structure of a Human GABA(A) Receptor Complex)

Berichtszeitraum: 2021-09-01 bis 2023-08-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Neuronal synapses are specialised cellular junctions that enable the transfer, modulation and storage of information in the nervous system. The normal physiology and function of neuronal circuits rely on balanced excitatory and inhibitory signalling. GABA(A) receptors are chloride permeable pentameric ligand-gated ion channels (pLGICs) and the principal mediators of fast inhibitory neurotransmission in the nervous system of vertebrates. Their dysfunction can lead to severe pathologies that include multiple types of epilepsy, insomnia, anxiety and neurodegeneration. As a consequence, GABA(A) receptors are targeted by a plethora of pharmacological agents with anti-convulsant, anxiolytic, analgesic, sedative and anaesthetic properties.

Structural studies have, so far, been focused on isolated GABA(A) receptors and on the mechanistic understanding of their rich pharmacology. In a cellular context, however, these receptors form complexes with multiple proteins that control their assembly, trafficking, cell surface localisation and internalisation. Such interactions are essential for GABAergic signalling. Therefore, the aim of my project was to explore the structural organisation of GABA(A) receptors bound to cell surface and intracellular binding partners.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

Structural studies on GABA(A) receptor complexes are particularly challenging. However, during the course of this project, I have successfully established methods for the production, purification, stabilisation and structural determination of a major GABA(A) receptor subtype bound to multiple partners, which led to the elucidation of novel GABA-ergic signalling mechanisms. The results obtained so far are being prepared for publication in peer-reviewed journals, in line with the fellowship open access guidelines.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

The Marie Curie postdoctoral fellowship support has allowed me to provide unprecedented mechanistic insights into the GABA-ergic neurotransmission. The structures I have determined also explain why certain GABA(A) receptor subtypes are targeted to synapses and others to extrasynaptic sites. In addition, I have also solved multiple structures of GABA(A) receptors bound to small molecule modulators, both physiological and synthetic, which can open up new avenues for therapeutic intervention.

Structure of a human GABA(A) receptor