Neurotransmitter-gated ion channels are responsible for fast chemical neurotransmission at synapses, i.e. the specialized chemical junction enabling the communication between excitable cells like neurons. Amongst these ion channels, the superfamily of pentameric ligand-gated ion channels (pLGIC) comprises chloride-permeable GABAA (GABAARs) and Glycine receptors (GlyRs), as well as excitatory nicotinic acetylcholine (nAChRs). GABAARs and GlyRs mediate fast inhibitory synaptic transmission, and are critical to maintain the excitation / inhibition balance of neurons, which controls their activity. The most prevalent neuronal nAChRs are the α7 homopentameric receptors and the α4β2 heteropentameric receptors, and are involved in various functions such as attention and memory.
Following the binding of their agonist (GABA for GABAARs, glycine for GlyRs and acetylcholine for nAChRs), these receptors undergo a conformational change leading to the opening their trasmembrane pore, enabling the flow of ions across the cell membrane, thereby producing changing the electrical activity of the cell. A wealth of structure-function studies has improved our understanding as to how pLGICs activate following the binding of agonist. However, besides their agonist-induced activation, most pLGICs display another fundamental pharmacological property: desensitization. Indeed, for most pLGICs, the sustained presence of the neurotransmitter will cause the channels to transit from the active open-channel agonist-bound conformation to a shut-channel, agonist-bound state called the desensitized state. Desensitization is thought to prevent the over-activation of receptors in pathological conditions, and can also lead to the reduction of postsynaptic current upon repetitive synaptic neurotransmitter release.
The structural basis and the physiological roles of pLGICs’ desensitization remain challenging questions to tackle, with potentially far-reaching applications like the development of drugs to treat pathologies in which pLGICs are involved, such as epilepsy, Alzheimer’s disease, schizophrenia, depression, chronic pain…
The overall objective of this project is to advance our understanding of the basic molecular events at play during pLGICs’ desensitization, in order to provide a better understanding of the desensitization process and provide proof-o-concepts for the development of drugs modulating the desensitization of pLGICs.
