A tale of ligands big and small: an update on how pentameric ligand-gated ion channels interact with agonists and proteins

Abstract

Pentameric ligand-gated ion channels (pLGICs, also known as Cys-loop receptors) are a large family of ion channels expressed in all Bilateria and in several groups of bacteria and archaea. They are activated by small-molecule neurotransmitters to mediate fast transmission at many central and peripheral nervous system synapses and are the target of several drugs and insecticides. Here we review recent advances in the field, focussing on new insights on the structure of the agonist-binding site and on newly discovered protein-protein interactions involving pLGICs.

Keywords: Ion channel; auxiliary subunit; chaperone; ligand binding; membrane protein function; toxin.

Figure 1

Overview of the α4β2 nAChR structure and two of its orthosteric ligand-binding pockets. (a) Top-down view of the heteromeric α4β2 structure with α4 and β2 subunits shown in cyan and grey, respectively. The bound ligand nicotine is shown in pink. (b)/(c) Close up views of the α4 (+) / β2 (-) (b) and β2 (+) / α4 (-) (c) binding sites with the same colouring scheme as in (a). All panels based on PDB entry 5KXI.

Figure 2

Examples of recently identified protein-protein interactions involving pLGICs. An exemplary pLGIC is depicted in yellow in both the ER (lower panel) and the plasma membrane (upper panel). New proposed interactions involving GABAR-specific toxins (green) targeting the ECD, nAChr α7 and the ER resident protein NACHO (pink), putative GABAR auxiliary subunits from the GARLH family (blue) that form a tripartite complex with GABARs and neuroligin-2 (grey). Interactions of the scaffolding protein gephyrin (orange) and GlyRs/GABARs have been deciphered in great detail and recently targeted using synthetic peptides.