Pentameric ligand-gated ion channels (pLGICs) are a major family of membrane receptors that mediate fast chemical transmission of nerve signals in the central and peripheral nervous system [1]. In vertebrates, the family encompasses the cationic selective acetylcholine and serotonine receptors, and the anionic selective glycine and γ-amino-butyric acid receptors. pLGICs are dynamic proteins that couple neurotransmitter binding in their extracellular-domain (ECD) to the opening of ion channels embedded in their transmembrane domain (TMD). The receptors share a common architecture with a large ECD and a TMD that is composed of four α-helices, named M1 to M4, that form a transmembrane pore bordered by the M2 helices (Figure 52a). The flow of ions across the membrane is inhibited by a structurally-diverse class of molecules including tricyclic antidepressants, local anaesthetics and certain transition metals that bind to the transmembrane pore. The molecular understanding of ion permeation is thus a central issue in the study of these ion channels.