Glutamate-gated Chloride Channels

Wolstenholme, Adrian J.

doi:10.1074/jbc.r112.406280

Cited by 213 publications

(184 citation statements)

References 96 publications

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“…In Drosophila melanogaster only one subunit is present, DmGluClα, which is responsible for the insect sensitivity to avermectin compounds [15]. The same seems to be the case in most insects studied [14]. Recently our understanding of the structural and functional properties of these receptors has made an enormous progress thanks to development of the crystallographic structure of Caenorabditis elegans GluClα subunit (CeGluClα) [16].…”

Section: Introductionmentioning

confidence: 99%

Identification and Functional Expression of a Glutamate- and Avermectin-Gated Chloride Channel from Caligus rogercresseyi, a Southern Hemisphere Sea Louse Affecting Farmed Fish

et al. 2014

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Parasitic sea lice represent a major sanitary threat to marine salmonid aquaculture, an industry accounting for 7% of world fish production. Caligus rogercresseyi is the principal sea louse species infesting farmed salmon and trout in the southern hemisphere. Most effective control of Caligus has been obtained with macrocyclic lactones (MLs) ivermectin and emamectin. These drugs target glutamate-gated chloride channels (GluCl) and act as irreversible non-competitive agonists causing neuronal inhibition, paralysis and death of the parasite. Here we report the cloning of a full-length CrGluClα receptor from Caligus rogercresseyi. Expression in Xenopus oocytes and electrophysiological assays show that CrGluClα is activated by glutamate and mediates chloride currents blocked by the ligand-gated anion channel inhibitor picrotoxin. Both ivermectin and emamectin activate CrGluClα in the absence of glutamate. The effects are irreversible and occur with an EC50 value of around 200 nM, being cooperative (nH = 2) for ivermectin but not for emamectin. Using the three-dimensional structure of a GluClα from Caenorabditis elegans, the only available for any eukaryotic ligand-gated anion channel, we have constructed a homology model for CrGluClα. Docking and molecular dynamics calculations reveal the way in which ivermectin and emamectin interact with CrGluClα. Both drugs intercalate between transmembrane domains M1 and M3 of neighbouring subunits of a pentameric structure. The structure displays three H-bonds involved in this interaction, but despite similarity in structure only of two these are conserved from the C. elegans crystal binding site. Our data strongly suggest that CrGluClα is an important target for avermectins used in the treatment of sea louse infestation in farmed salmonids and open the way for ascertaining a possible mechanism of increasing resistance to MLs in aquaculture industry. Molecular modeling could help in the design of new, more efficient drugs whilst functional expression of the receptor allows a first stage of testing of their efficacy.

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Section: Introductionmentioning

confidence: 99%

Identification and Functional Expression of a Glutamate- and Avermectin-Gated Chloride Channel from Caligus rogercresseyi, a Southern Hemisphere Sea Louse Affecting Farmed Fish

et al. 2014

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“…Recently, the X-ray structure of a Caenorhabditis elegans GluCl channel has been solved [41], the first three-dimensional structure for a Cys-loop ligand-gated channel. Exhaustive reviews on the structure and properties of these channels have been published [42-44]. …”

Section: Glutamate-gated Chloride Channelsmentioning

confidence: 99%

Ion Channels and Drug Transporters as Targets for Anthelmintics

Greenberg

2014

Curr Clin Micro Rpt

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Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance.

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“…The main active ingredient, which is effective against nematodes (i.e., eprinomectin), belongs to the avermectin family and it affects pathogens by irreversibly opening the glutamate-gated chloride ion channels and inducing cell hyperpolarization (Wolstenholme, 2012). This product has been tested in domestic cats for safety and efficacy against natural nematode and tapeworm infections, and was demonstrated highly efficacious against ascarids (i.e., T. cati and Toxascaris leonina), hookworms (i.e., A. tubaeforme and Ancylostoma braziliense) and Capillaria (syn.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Broadline® spot-on against Aelurostrongylus abstrusus and Troglostrongylus brevior lungworms in naturally infected cats from Italy

Giannelli

Brianti

Varcasia

et al. 2015

Veterinary Parasitology

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The increasing reports of Aelurostrongylus abstrusus infection and the new information on Troglostrongylus brevior have spurred the interest of the scientific community towards the research of pharmaceutical compounds effective against both pathogens. A novel topical combination of fipronil, (S)-methoprene, eprinomectin and praziquantel (Broadline®, Merial) has been released for the treatment of a variety of feline parasitic infections. The present study reports the efficacy of this spot-on in treating cats naturally infected by feline lungworms. Client owned cats (n=191) were enrolled from three geographical areas of Italy and faecal samples were examined by floatation and Baermann techniques. Twenty-three individuals were positive for L1 of A. abstrusus (n=18) or T. brevior (n=3) or for both species (n=2) and they were topically treated with Broadline®. Seventeen of them were also concomitantly infected by other parasites. Four weeks after treatment, faecal samples were collected and examined to assess the efficacy of a single administration of the product. Based on lungworm larvae counts, the efficacy of the treatment was 90.5% or 100% for A. abstrusus or T. brevior, respectively. Cats released significantly lower amounts of lungworm larvae after treatment compared to pre-treatment (p<0.0001). All but three cats were negative for other nematodes after treatment and all cats recovered from respiratory signs. Results of this study indicate that a single administration of the topical combination fipronil, (S)-methoprene, eprinomectin and praziquantel is effective and safe for the treatment of A. abstrusus and/or T. brevior infections in cats living under field conditions.

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Glutamate-gated Chloride Channels

Cited by 213 publications

References 96 publications

Identification and Functional Expression of a Glutamate- and Avermectin-Gated Chloride Channel from Caligus rogercresseyi, a Southern Hemisphere Sea Louse Affecting Farmed Fish

Identification and Functional Expression of a Glutamate- and Avermectin-Gated Chloride Channel from Caligus rogercresseyi, a Southern Hemisphere Sea Louse Affecting Farmed Fish

Ion Channels and Drug Transporters as Targets for Anthelmintics

Efficacy of Broadline® spot-on against Aelurostrongylus abstrusus and Troglostrongylus brevior lungworms in naturally infected cats from Italy

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