Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2022 Mar 01;1796:1264-1279. doi: 10.1111/bph.15703.
Show Gene links
Show Anatomy links
Pharmacological characterization of novel heteromeric GluCl subtypes from Caenorhabditis elegans and parasitic nematodes.
Lamassiaude N
,
Courtot E
,
Corset A
,
Charvet CL
,
Neveu C
.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: Macrocyclic lactones are the most widely used broad-spectrum anthelmintic drugs for the treatment of parasitic nematodes affecting both human and animal health. Macrocyclic lactones are agonists of the nematode glutamate-gated chloride channels (GluCls). However, for many important nematode species, the GluCls subunit composition and pharmacological properties remain largely unknown. To gain new insights into GluCl diversity and mode of action of macrocyclic lactones, we identified and pharmacologically characterized receptors made of highly conserved GluCl subunits from the model nematode Caenorhabditis elegans, the human filarial nematode Brugia malayi and the horse parasite Parascaris univalens.
EXPERIMENTAL APPROACH: AVR-14, GLC-2, GLC3 and GLC-4 are the most conserved GluCl subunits throughout the Nematoda phylum. For each nematode species, we investigated the ability of these subunits to form either homomeric or heteromeric GluCls when expressed in Xenopus laevis oocytes and carried out detailed pharmacological characterization of the functional channels.
KEY RESULTS: A total of 14 GluCls were functionally reconstituted, and heteromers formation was inferred from pharmacological criteria. The GLC-2 subunit plays a pivotal role in the composition of heteromeric GluCls in nematodes. We also found a novel GluCl subtype, combining GLC-2/GLC-3 subunits, for which a high concentration of the anthelmintics ivermectin and moxidectin reversibly potentiates glutamate-induced response.
CONCLUSION AND IMPLICATIONS: This study brings new insights into the diversity of GluCl subtypes in nematodes and promotes novel drug targets for the development of the next generation of anthelmintic compounds.
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Ion channels.
2021, Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Ion channels.
2021,
Pubmed
Atif,
Effects of glutamate and ivermectin on single glutamate-gated chloride channels of the parasitic nematode H. contortus.
2017,
Pubmed
Atif,
GluClR-mediated inhibitory postsynaptic currents reveal targets for ivermectin and potential mechanisms of ivermectin resistance.
2019,
Pubmed
,
Xenbase
Beech,
Nematode parasite genes: what's in a name?
2010,
Pubmed
Bendtsen,
Improved prediction of signal peptides: SignalP 3.0.
2004,
Pubmed
Bianchi,
Heterologous expression of C. elegans ion channels in Xenopus oocytes.
2006,
Pubmed
,
Xenbase
Blanchard,
Deciphering the molecular determinants of cholinergic anthelmintic sensitivity in nematodes: When novel functional validation approaches highlight major differences between the model Caenorhabditis elegans and parasitic species.
2018,
Pubmed
,
Xenbase
Blaxter,
The evolution of parasitism in Nematoda.
2015,
Pubmed
Blaxter,
A molecular evolutionary framework for the phylum Nematoda.
1998,
Pubmed
Boulin,
Functional reconstitution of Haemonchus contortus acetylcholine receptors in Xenopus oocytes provides mechanistic insights into levamisole resistance.
2011,
Pubmed
,
Xenbase
Boulin,
Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor.
2008,
Pubmed
,
Xenbase
Boyle,
Gene manipulation in parasitic helminths.
2003,
Pubmed
Campbell,
History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents.
2012,
Pubmed
Cao,
Comprehensive single-cell transcriptional profiling of a multicellular organism.
2017,
Pubmed
Charvet,
Nicotine-sensitive acetylcholine receptors are relevant pharmacological targets for the control of multidrug resistant parasitic nematodes.
2018,
Pubmed
,
Xenbase
Cheeseman,
High-affinity ivermectin binding to recombinant subunits of the Haemonchus contortus glutamate-gated chloride channel.
2001,
Pubmed
Cook,
Caenorhabditis elegans ivermectin receptors regulate locomotor behaviour and are functional orthologues of Haemonchus contortus receptors.
2006,
Pubmed
Courtot,
Functional Characterization of a Novel Class of Morantel-Sensitive Acetylcholine Receptors in Nematodes.
2015,
Pubmed
,
Xenbase
Cully,
Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans.
1994,
Pubmed
,
Xenbase
Cully,
Molecular biology and electrophysiology of glutamate-gated chloride channels of invertebrates.
1996,
Pubmed
,
Xenbase
Curtis,
Experimental design and analysis and their reporting II: updated and simplified guidance for authors and peer reviewers.
2018,
Pubmed
Degani-Katzav,
Subunit stoichiometry and arrangement in a heteromeric glutamate-gated chloride channel.
2016,
Pubmed
Dent,
avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans.
1997,
Pubmed
Dent,
The genetics of ivermectin resistance in Caenorhabditis elegans.
2000,
Pubmed
Gokbulut,
Anthelmintic drugs used in equine species.
2018,
Pubmed
Gouy,
SeaView version 4: A multiplatform graphical user interface for sequence alignment and phylogenetic tree building.
2010,
Pubmed
Hernando,
Caenorhabditis elegans neuromuscular junction: GABA receptors and ivermectin action.
2014,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Holden-Dye,
Actions of glutamate and ivermectin on the pharyngeal muscle of Ascaridia galli: a comparative study with Caenorhabditis elegans.
2006,
Pubmed
Horoszok,
GLC-3: a novel fipronil and BIDN-sensitive, but picrotoxinin-insensitive, L-glutamate-gated chloride channel subunit from Caenorhabditis elegans.
2001,
Pubmed
,
Xenbase
Hutter,
GExplore 1.4: An expanded web interface for queries on Caenorhabditis elegans protein and gene function.
2016,
Pubmed
Kaplan,
An inconvenient truth: global worming and anthelmintic resistance.
2012,
Pubmed
Laing,
Ivermectin - Old Drug, New Tricks?
2017,
Pubmed
Lamassiaude,
The molecular targets of ivermectin and lotilaner in the human louse Pediculus humanus humanus: New prospects for the treatment of pediculosis.
2021,
Pubmed
Lees,
The efficacy of emamectin benzoate against infestations of Lepeophtheirus salmonis on farmed Atlantic salmon (Salmo salar L) in Scotland, 2002-2006.
2008,
Pubmed
Liu,
In vivo imaging of transgenic Brugia malayi.
2020,
Pubmed
Madeira,
The EMBL-EBI search and sequence analysis tools APIs in 2019.
2019,
Pubmed
Martin,
Resistance to pyrantel embonate and efficacy of fenbendazole in Parascaris univalens on Swedish stud farms.
2018,
Pubmed
Matthews,
Progress in the development of subunit vaccines for gastrointestinal nematodes of ruminants.
2016,
Pubmed
McCavera,
An ivermectin-sensitive glutamate-gated chloride channel from the parasitic nematode Haemonchus contortus.
2009,
Pubmed
,
Xenbase
McCoy,
RNA interference in adult Ascaris suum--an opportunity for the development of a functional genomics platform that supports organism-, tissue- and cell-based biology in a nematode parasite.
2015,
Pubmed
NULL,
Global programme to eliminate lymphatic filariasis: progress report, 2016.
2017,
Pubmed
Nielsen,
Parascaris univalens--a victim of large-scale misidentification?
2014,
Pubmed
Njue,
Mutations in the extracellular domains of glutamate-gated chloride channel alpha3 and beta subunits from ivermectin-resistant Cooperia oncophora affect agonist sensitivity.
2004,
Pubmed
,
Xenbase
Peregrine,
Anthelmintic resistance in important parasites of horses: does it really matter?
2014,
Pubmed
Pullan,
Global numbers of infection and disease burden of soil transmitted helminth infections in 2010.
2014,
Pubmed
Ramaiah,
Progress and impact of 13 years of the global programme to eliminate lymphatic filariasis on reducing the burden of filarial disease.
2014,
Pubmed
Reinemeyer,
Parasitism and colic.
2009,
Pubmed
Sallé,
Compilation of 29 years of postmortem examinations identifies major shifts in equine parasite prevalence from 2000 onwards.
2020,
Pubmed
Schultz,
SMART, a simple modular architecture research tool: identification of signaling domains.
1998,
Pubmed
Selkirk,
The development of RNA interference (RNAi) in gastrointestinal nematodes.
2012,
Pubmed
Song,
Development of an in vivo RNAi protocol to investigate gene function in the filarial nematode, Brugia malayi.
2010,
Pubmed
Storey,
Utilization of computer processed high definition video imaging for measuring motility of microscopic nematode stages on a quantitative scale: "The Worminator".
2014,
Pubmed
Sönnichsen,
Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans.
2005,
Pubmed
Vassilatis,
Genetic and biochemical evidence for a novel avermectin-sensitive chloride channel in Caenorhabditis elegans. Isolation and characterization.
1997,
Pubmed
,
Xenbase
Wever,
The Validation of Nematode-Specific Acetylcholine-Gated Chloride Channels as Potential Anthelmintic Drug Targets.
2015,
Pubmed
Williamson,
Candidate anthelmintic resistance-associated gene expression and sequence polymorphisms in a triple-resistant field isolate of Haemonchus contortus.
2011,
Pubmed
Williamson,
The cys-loop ligand-gated ion channel gene family of Brugia malayi and Trichinella spiralis: a comparison with Caenorhabditis elegans.
2007,
Pubmed
Yates,
An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis.
2004,
Pubmed
,
Xenbase
de Moraes,
FDA-Approved Antiparasitic Drugs in the 21st Century: A Success for Helminthiasis?
2020,
Pubmed