Structure of a Human GABA(A) Receptor Complex

Project Information

GABAARComp

Grant agreement ID: 897707

DOI

10.3030/897707

Project closed

EC signature date 23 March 2020

Start date 1 September 2021

End date 31 August 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 212 933,76

EU contribution

€ 212 933,76

Coordinated by

UNITED KINGDOM RESEARCH AND INNOVATION
United Kingdom

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

Reporting period: 2021-09-01 to 2023-08-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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