About the Project
Chemical synapses are cellular connections that define the organization and function of neuronal circuits and, as a result, the fundamental ability of the brain to acquire, process and store information. Two small molecules, glutamate (excitatory) and gamma-aminobutyric acid (GABA, inhibitory) mediate the majority of synaptic transmission in the vertebrate central nervous system. These bind ligand-gated ion channels and G-protein coupled receptors, to initiate neuronal signalling events.
The steady progress in the structural biology of membrane proteins during the past decade has provided a wealth of information on purified neurotransmitter receptors. We know how most of them look, and can imagine how they function. In a physiological context, however, these receptors do not work, or even exist, in isolation. They form merely the cores of large protein assemblies, including extracellular, transmembrane and intracellular molecules, which play essential roles throughout the "life-cycle" of synapses. A structure-based, mechanistic understanding of such assemblies is currently lacking.
Your project will focus on the structural and functional analysis of neurotransmitter receptor supra-molecular complexes. These span the synaptic cleft to physically connect neurotransmitter release sites in the pre-synaptic membrane with receptors on the post-synaptic side. Multiple options are available, built around the expertise available in our group on GABAA and glutamate ligand-gated ion channel families. Enquiries are encouraged, to discuss further details. This is an excellent opportunity to acquire experience in human membrane protein biochemistry and modern structural biology, including single-particle cryo-EM, cryo-electron tomography and plasma-FIB milling of brain tissue lamellae. Structural work will be combined with biophysical analyses, electrophysiology and super-resolution fluorescence microscopy. The LMB provides all the infrastructure required and an outstanding training environment for these techniques.
Our ongoing work with industry partners offers realistic opportunities to translate academic discoveries into real-life therapies.
Funding Notes
Competition Funded PhD Project (Students Worldwide)
References
- Elegheert J, Kakegawa W, Clay JE, Shanks NF, Behiels E, Matsuda K, Kohda K, Miura E, Rossmann M, Mitakidis N, Motohashi J, Chang VT, Siebold C, Greger I, Nakagawa T, Yuzaki M., Aricescu AR (2016) Structural Basis for Integration of GluD Receptors within Synaptic Organizer Complexes. Science 353:295-299.
- Suzuki K, Elegheert J, Song I, Sasakura H, Senkov O, Matsuda K, Kakegawa W, Clayton AJ, Chang VT, Ferrer-Ferrer M, Miura E, Kaushik R, Ikeno M, Morioka Y, Takeuchi Y, Shimada T, Otsuka S, Stoyanov S, Watanabe M, Takeuchi K, Dityatev A, Aricescu AR and Yuzaki M. A synthetic synaptic organizer protein restores glutamatergic neuronal circuits. (2020) Science 369:eabb4853.
- Elegheert J, Cvetkovska V, Clayton AJ, Heroven C, Vennekens KM, Smukowski SN, Regan MC, Jia W, Smith AC, Furukawa H, Savas JN, de Wit J, Begbie J, Craig AM, Aricescu AR. (2017) Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins. Neuron 96:242-244.
- Masiulis S, Desai R, Uchański T, Martin IS, Laverty D, Karia D, Malinauskas T, Zivanov J, Pardon E, Kotecha A, Steyaert J, Miller KW, Aricescu AR. (2019) GABAA receptor signalling mechanisms revealed by structural pharmacology. Nature 565:454-459.
- Sente A, Desai R, Naydenova K, Malinauskas T, Jounaidi Y, Miehling J, Zhou X, Masiulis S, Hardwick SW, Chirgadze DY, Miller KW and Aricescu AR. (2022) Differential assembly diversifies GABAA receptor structures and signalling. Nature 604:190-194.
- Piot L, Heroven C, Bossi S, Zamith J, Malinauskas T, Johnson C, Wennagel D, Stroebel D, Charrier C, Aricescu AR, Mony L, Paoletti P. (2023) GluD1 binds GABA and controls inhibitory plasticity. Science 382:1389-1394.
