Trapping of ivermectin by a pentameric ligand-gated ion channel upon open-to-closed isomerization.

ABSTRACT: Ivermectin (IVM) is a broad-spectrum anthelmintic drug used to treat human parasitic diseases like river blindness and lymphatic filariasis. By activating invertebrate pentameric glutamate-gated chloride channels (GluCl receptors; GluClRs), IVM induces sustained chloride influx and long-lasting membrane hyperpolarization that inhibit neural excitation in nematodes. Although IVM activates the C. elegans heteromeric GluCl?/? receptor, it cannot activate a homomeric receptor composed of the C. elegans GluCl? subunits. To understand this incapability, we generated a homopentameric ?7-GluCl? chimeric receptor that consists of an extracellular ligand-binding domain of an ?7 nicotinic acetylcholine receptor known to be potentiated by IVM, and a chloride-selective channel domain assembled from GluCl? subunits. Application of IVM prior to acetylcholine inhibited the responses of the chimeric ?7-GluCl?R. Adding IVM to activated ?7-GluCl?Rs, considerably accelerated the decline of ACh-elicited currents and stabilized the receptors in a non-conducting state. Determination of IVM association and dissociation rate constants and recovery experiments suggest that, following initial IVM binding to open ?7-GluCl?Rs, the drug induces a conformational change and locks the ion channel in a closed state for a long duration. We further found that IVM also inhibits the activation by glutamate of a homomeric receptor assembled from the C. elegans full-length GluCl? subunits.

SUBMITTER: Degani-Katzav N 

PROVIDER: S-EPMC5317004 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature