title: Caenorhabditis elegans ivermectin receptors regulate locomotor behaviour and are functional orthologues of Haemonchus contortus receptors.
abstract: The target site for the anthelmintic action of ivermectin is a family of nematode glutamate-gated chloride channel alpha subunits (GluClalpha) that bind the drug with high affinity and mediate its potent paralytic action. Whilst the action of ivermectin on the pharyngeal muscle of nematodes is relatively well understood, its effect on locomotor activity is less clear. Here we use RNAi and gene knockouts to show that four GluClalpha subunits are involved in regulating the pattern of locomotor activity in Caenorhabditis elegans. A Haemonchus contortus orthologue of these subunits, HcGluClalpha3, has been shown to be expressed in the motor nervous system and here we have shown that it is a functional, as well as a structural, orthologue by virtue of the observation that it can restore normal motor movement in the C. elegans GluClalpha mutant, avr-14(ad1032), when expressed under the control of the avr-14 promoter. This supports the contention that ivermectin exerts its paralytic action on parasitic nematodes through activation of GluCl channels in the motor nervous system. Furthermore, functional complementation in C. elegans provides a method to further the understanding of this important class of anthelmintic targets.
authors.affiliation: Neurosciences Research Group, School of Biological Sciences, Bassett Crescent East, University of Southampton, Southampton SO16 7PX, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Cook
authors.forename: Nathalie
authors.initials: N
authors.lastname: Aptel
authors.forename: Virginia
authors.initials: V
authors.lastname: Portillo
authors.forename: Elodie
authors.initials: E
authors.lastname: Siney
authors.forename: Rajinder
authors.initials: R
authors.lastname: Sihota
authors.forename: Lindy
authors.initials: L
authors.lastname: Holden-Dye
authors.forename: Adrian
authors.initials: A
authors.lastname: Wolstenholme
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000378:metabolism* / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006189:Haemonchus / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D007559:Ivermectin / Q000378:metabolism* / Q000494:pharmacology; D009068:Movement / Q000187:drug effects; D034622:RNA Interference; D017470:Receptors, Glutamate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000871:Anthelmintics; D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels; D017470:Receptors, Glutamate; C109777:glutamate-gated chloride channels; D007559:Ivermectin