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.
Identification and functional expression of a glutamate- and avermectin-gated chloride channel from Caligus rogercresseyi, a southern Hemisphere sea louse affecting farmed fish.
Cornejo I
,
Andrini O
,
Niemeyer MI
,
Marabolí V
,
González-Nilo FD
,
Teulon J
,
Sepúlveda FV
,
Cid LP
.
???displayArticle.abstract???
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 EC(50) value of around 200 nM, being cooperative (n(H) = 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.
Bode,
Analysis of hyperekplexia mutations identifies transmembrane domain rearrangements that mediate glycine receptor activation.
2013, Pubmed
Bode,
Analysis of hyperekplexia mutations identifies transmembrane domain rearrangements that mediate glycine receptor activation.
2013,
Pubmed
Bravo,
Efficacy of the treatments used for the control of Caligus rogercresseyi infecting Atlantic salmon, Salmo salar L., in a new fish-farming location in Region XI, Chile.
2013,
Pubmed
Calimet,
A gating mechanism of pentameric ligand-gated ion channels.
2013,
Pubmed
Cheeseman,
High-affinity ivermectin binding to recombinant subunits of the Haemonchus contortus glutamate-gated chloride channel.
2001,
Pubmed
Cheng,
Energetics and ion permeation characteristics in a glutamate-gated chloride (GluCl) receptor channel.
2012,
Pubmed
Corringer,
Structure and pharmacology of pentameric receptor channels: from bacteria to brain.
2012,
Pubmed
Costello,
Ecology of sea lice parasitic on farmed and wild fish.
2006,
Pubmed
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
Cully,
Identification of a Drosophila melanogaster glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin.
1996,
Pubmed
,
Xenbase
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
Etter,
Picrotoxin blockade of invertebrate glutamate-gated chloride channels: subunit dependence and evidence for binding within the pore.
1999,
Pubmed
,
Xenbase
Etter,
An amino acid substitution in the pore region of a glutamate-gated chloride channel enables the coupling of ligand binding to channel gating.
1996,
Pubmed
,
Xenbase
Forrester,
Cloning, sequencing, and developmental expression levels of a novel glutamate-gated chloride channel homologue in the parasitic nematode Haemonchus contortus.
1999,
Pubmed
Forrester,
Haemonchus contortus: HcGluCla expressed in Xenopus oocytes forms a glutamate-gated ion channel that is activated by ibotenate and the antiparasitic drug ivermectin.
2003,
Pubmed
,
Xenbase
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Horsberg,
Avermectin use in aquaculture.
2012,
Pubmed
Huang,
Simultaneous amplification of 5' and 3' cDNA ends based on template-switching effect and inverse PCR.
2006,
Pubmed
Igboeli,
Sea lice population and sex differences in P-glycoprotein expression and emamectin benzoate resistance on salmon farms in the Bay of Fundy, New Brunswick, Canada.
2014,
Pubmed
Jones,
The cys-loop ligand-gated ion channel superfamily of the honeybee, Apis mellifera.
2006,
Pubmed
Jones,
The cys-loop ligand-gated ion channel gene superfamily of the red flour beetle, Tribolium castaneum.
2007,
Pubmed
Jones,
The cys-loop ligand-gated ion channel gene superfamily of the nematode, Caenorhabditis elegans.
2008,
Pubmed
Kane,
Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin.
2000,
Pubmed
,
Xenbase
Kwon,
A point mutation in a glutamate-gated chloride channel confers abamectin resistance in the two-spotted spider mite, Tetranychus urticae Koch.
2010,
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
Lynagh,
A glycine residue essential for high ivermectin sensitivity in Cys-loop ion channel receptors.
2010,
Pubmed
Lynagh,
Ivermectin binding sites in human and invertebrate Cys-loop receptors.
2012,
Pubmed
Miledi,
Chloride current induced by injection of calcium into Xenopus oocytes.
1984,
Pubmed
,
Xenbase
Phillips,
Scalable molecular dynamics with NAMD.
2005,
Pubmed
Raymond,
Novel animal-health drug targets from ligand-gated chloride channels.
2002,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Sastry,
Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments.
2013,
Pubmed
Smart,
HOLE: a program for the analysis of the pore dimensions of ion channel structural models.
1996,
Pubmed
Takeuchi,
A study of the action of picrotoxin on the inhibitory neuromuscular junction of the crayfish.
1969,
Pubmed
Torrissen,
Salmon lice--impact on wild salmonids and salmon aquaculture.
2013,
Pubmed
Tribble,
Identification of the genes encoding for putative gamma aminobutyric acid (GABA) and glutamate-gated chloride channel (GluCl) alpha receptor subunits in sea lice (Lepeophtheirus salmonis).
2007,
Pubmed
Vassilatis,
Genetic and biochemical evidence for a novel avermectin-sensitive chloride channel in Caenorhabditis elegans. Isolation and characterization.
1997,
Pubmed
,
Xenbase
Wolstenholme,
Drug resistance in veterinary helminths.
2004,
Pubmed
Wolstenholme,
Glutamate-gated chloride channels.
2012,
Pubmed