GABAARComp · Structure of a Human GABA(A) Receptor Complex
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-09-01 → 2023-08-31
- EU contribution
- €212,934
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Structure of a Human GABA(A) Receptor Complex
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.
Data: CORDIS, © European Union
Project objective
GABA(A)Rs are the principal neurotransmitter receptors at the inhibitory synapses. The majority of these receptors are anchored at the inhibitory postsynaptic compartment by the central scaffolding function of gephyrin. A dysfunctional receptor clustering by gephyrin leads to abnormal neurotransmission and neurodevelopmental disorders, including anxiety disorders and epilepsy. Recent advances in the structural studies, most recently by cryo-electron microscopy (cryo-EM), have elucidated several heteropentameric GABA(A)R structures. All of these illustrate receptors in isolation. However, in a physiological synaptic context, GABAARs exist and function in close association the auxiliary protein LFPLH4 as well as with anchoring proteins including gephyrin, collybistin (CB) and the adhesion molecule neuroligin 2 (NL2). To understand the architecture and function of this fundamental complex, I will work on the structural elucidation of the human GABA(A)R-gephyrin-CB-NL2 supramolecular complex by single-particle cryo-EM. Structural studies will be followed by validation using additional biochemical, biophysical and electrophysiological analysis of mutant constructs. These data will not only provide the first insights into the supra-molecular organization of a major human neurotransmitter receptor. As the dysfunctional GABAergic neurotransmission manifest itself in lethal neurodevelopmental disorders such as Alzheimer’s and also epilepsy, structural insight into the central complex will also help to understand the molecular basis of these disorders.
Original text from CORDIS.
Participants
- UNITED KINGDOM RESEARCH AND INNOVATION · SWINDONCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union