title: 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 GluClα/β receptor, it cannot activate a homomeric receptor composed of the C. elegans GluClβ subunits. To understand this incapability, we generated a homopentameric α7-GluClβ 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 GluClβ subunits. Application of IVM prior to acetylcholine inhibited the responses of the chimeric α7-GluClβR. Adding IVM to activated α7-GluClβRs, 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-GluClβRs, 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 GluClβ subunits.
authors.affiliation: Laboratory of Ion Channels, The Mina and Everard Goodman Faculty of Life Sciences and The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 52900, Israel.
authors.forename: Nurit
authors.initials: N
authors.lastname: Degani-Katzav
authors.affiliation: Laboratory of Ion Channels, The Mina and Everard Goodman Faculty of Life Sciences and The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 52900, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Klein
authors.affiliation: Laboratory of Ion Channels, The Mina and Everard Goodman Faculty of Life Sciences and The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 52900, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Har-Even
authors.affiliation: Laboratory of Ion Channels, The Mina and Everard Goodman Faculty of Life Sciences and The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 52900, Israel.
authors.forename: Revital
authors.initials: R
authors.lastname: Gortler
authors.affiliation: Laboratory of Ion Channels, The Mina and Everard Goodman Faculty of Life Sciences and The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 52900, Israel.
authors.forename: Ruthi
authors.initials: R
authors.lastname: Tobi
authors.affiliation: Laboratory of Ion Channels, The Mina and Everard Goodman Faculty of Life Sciences and The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 52900, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Paas
mesh_terms: D000109:Acetylcholine / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D018118:Chloride Channels; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D015640:Ion Channel Gating; D007536:Isomerism; D007559:Ivermectin / Q000737:chemistry* / Q000494:pharmacology; D058446:Ligand-Gated Ion Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D055503:Protein Multimerization; D013329:Structure-Activity Relationship
chemical_list: D018118:Chloride Channels; D058446:Ligand-Gated Ion Channels; D008024:Ligands; C109777:glutamate-gated chloride channels; D007559:Ivermectin; D000109:Acetylcholine