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Sci Rep ; 7: 42481, 2017 02 20.
Article in English | MEDLINE | ID: mdl-28218274

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 GluClα/ß receptor, it cannot activate a homomeric receptor composed of the C. elegans GluClß subunits. To understand this incapability, we generated a homopentameric α7-GluClß chimeric receptor that consists of an extracellular ligand-binding domain of an α7 nicotinic acetylcholine receptor known to be potentiated by IVM, and a chloride-selective channel domain assembled from GluClß subunits. Application of IVM prior to acetylcholine inhibited the responses of the chimeric α7-GluClßR. Adding IVM to activated α7-GluClßRs, 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 α7-GluClßRs, 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 GluClß subunits.


Subject(s)
Ivermectin/chemistry , Ligand-Gated Ion Channels/chemistry , Acetylcholine/chemistry , Acetylcholine/pharmacology , Animals , CHO Cells , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Cell Membrane/metabolism , Chloride Channels , Cricetulus , Dose-Response Relationship, Drug , Gene Expression , Ion Channel Gating , Isomerism , Ivermectin/pharmacology , Ligand-Gated Ion Channels/genetics , Ligand-Gated Ion Channels/metabolism , Ligands , Models, Molecular , Molecular Conformation , Protein Multimerization , Structure-Activity Relationship
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