Every time you learn something new, a microscopic gateway in your brain called an AMPA receptor flips open in a fraction of a millisecond. These receptors are the workhorses of fast communication between neurons, and when they malfunction, the result can be epilepsy, stroke damage, or neurodegenerative disease. What researchers still do not understand is how the receptor’s many helper proteins—its auxiliary subunits—control its opening and closing, and how drugs might target specific states of the receptor. This project will use cryo-electron microscopy, computer simulations, and single-channel recordings to map the receptor’s moving parts in atomic detail, including its interactions with lipids and with experimental neurotherapeutics. The work is fundamental science: it aims to explain how a core signalling machine in the brain actually works. If successful, it will produce a comprehensive kinetic model of receptor activation and reveal the precise conformational states that drugs lock onto—information that could eventually guide structure-based design of more selective treatments for neurological disorders.
View original technical description
AMPA receptor (AMPAR) operation underlies learning, while receptor malfunction is associated with various diseases. Their uniquely versatile signalling arises from numerous auxiliary subunits that assemble into functionally diverse receptor super-complexes. The combination and stoichiometry of these components, and how they shape neuronal response properties, remains a central open question. We will elucidate the pathways leading to activation of a predominant AMPAR, building on our cryo-EM structures of this receptor, associated with two structurally diverse auxiliary subunits. Using cryo-EM, MD simulations and single-channel recordings, we will assess the differential contribution of core- and auxiliary subunits to the receptor’s characteristic activation time course. We will also investigate the mechanism of leading neurotherapeutics on gating, capitalising on our AMPAR structures associated with these ligands, and study the role of the receptor’s lipid environment through reconstitution into liposomes. We will complement these studies with time-resolved cryo-EM of gating intermediates, and structures of native AMPAR complexes, isolated from mammalian synapses. These experiments will uncover the principles underlying AMPAR organisation and activation. We will derive a comprehensive kinetic model, delineating how activation is modulated by auxiliary subunits, lipids and neurotherapeutics. Elucidating the conformational states selectively targeted by these ligands will facilitate targeted structure-based drug design.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know