Cys-loop receptors are
neurotransmitter-gated
ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as
parasitic infections. Members of this
ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their
ligand and ion selectivity. Structural information for
Cys-loop receptors comes from several sources including electron microscopic studies of the
nicotinic acetylcholine receptor, high-resolution X-ray structures of extracellular domains and X-ray structures of bacterial orthologues. In 2011 our group published structures of the Caenorhabditis elegans
glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist
ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic
Cys-loop receptor, the basis for
anion selectivity and channel block, and the mechanism by which
ivermectin and related molecules stabilize the open state and potentiate
neurotransmitter binding. However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut
ion channel gate, the transitions between the closed/resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane,
ion channel domain. Here we present two conformationally distinct structures of C. elegans GluCl in the absence of
ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid-body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by
phospholipids.