The transmission of information from one neuron to the next is mediated by a large set of neurotransmitter receptors. Among those, the project aimed at understanding better one class of receptors named pentameric ligand-gated ion channels. Why ? Because they participate in many physiological functions (voluntary motion, memory, sleep, anxiety, reward, pain, ...) are involved in numerous pathologies (epilepsy, Parkinson and Alzheimer diseases, ...) and are the targets of a legion of psycho-active and therapeutic compounds (including nicotine, antidepressants, antiemetics, anesthetics, ...). How ? By looking at the molecular structure of those receptors to decipher how drugs bind to them and how this binding eventually yield a signalling output.
In terms of methods, we have optimised ways of obtaining large quantities of pure and stable receptors, which enables their imaging by cryo-electron microscopy. We also participated in making that imaging easier when the receptors are embedded into a tiny discs made of lipids.
In terms of applications, we have shown how serotonin receptors activate and how a panel of antiemetics (including tropisetron and palonosetron) or an antidepressant (vortioxetine) inhibit them. We have also shown how agonists, and in particular nicotine, binds to the muscle-type acetylcholine receptor. We have identified that agonist-bound receptors (both the serotonin and the acetylcholine ones) can exist in intermediate states. We have described how the receptors block or allow the passage of ions (the signalling) through a gate, using a mechanism of wetting/dewetting.
Taken together, the project has shed light onto the molecular mechanism of action and the structural pharmacology of pentameric-ligand channels and has helped the development of techniques for their study.
