Periodic Reporting for period 1 - GABAARComp (Structure of a Human GABA(A) Receptor Complex)
Reporting period: 2021-09-01 to 2023-08-31
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.
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.
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.
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.