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
2011 Nov 01;1645:1421-32. doi: 10.1111/j.1476-5381.2011.01420.x.
Show Gene links
Show Anatomy links
Functional reconstitution of Haemonchus contortus acetylcholine receptors in Xenopus oocytes provides mechanistic insights into levamisole resistance.
Boulin T
,
Fauvin A
,
Charvet CL
,
Cortet J
,
Cabaret J
,
Bessereau JL
,
Neveu C
.
???displayArticle.abstract???
The cholinergic agonist levamisole is widely used to treat parasitic nematode infestations. This anthelmintic drug paralyses worms by activating a class of levamisole-sensitive acetylcholine receptors (L-AChRs) expressed in nematode muscle cells. However, levamisole efficacy has been compromised by the emergence of drug-resistant parasites, especially in gastrointestinal nematodes such as Haemonchus contortus. We report here the first functional reconstitution and pharmacological characterization of H. contortus L-AChRs in a heterologous expression system.In the free-living nematode Caenorhabditis elegans, five AChR subunit and three ancillary protein genes are necessary in vivo and in vitro to synthesize L-AChRs. We have cloned the H. contortus orthologues of these genes and expressed them in Xenopus oocytes. We reconstituted two types of H. contortus L-AChRs with distinct pharmacologies by combining different receptor subunits.The Hco-ACR-8 subunit plays a pivotal role in selective sensitivity to levamisole. As observed with C. elegans L-AChRs, expression of H. contortus receptors requires the ancillary proteins Hco-RIC-3, Hco-UNC-50 and Hco-UNC-74. Using this experimental system, we demonstrated that a truncated Hco-UNC-63 L-AChR subunit, which was specifically detected in a levamisole-resistant H. contortus isolate, but not in levamisole-sensitive strains, hampers the normal function of L-AChRs, when co-expressed with its full-length counterpart.We provide the first functional evidence for a putative molecular mechanism involved in levamisole resistance in any parasitic nematode. This expression system will provide a means to analyse molecular polymorphisms associated with drug resistance at the electrophysiological level.
Aceves,
The mechanism of the paralysing action of tetramisole on Ascaris somatic muscle.
1970, Pubmed
Aceves,
The mechanism of the paralysing action of tetramisole on Ascaris somatic muscle.
1970,
Pubmed
Almedom,
An ER-resident membrane protein complex regulates nicotinic acetylcholine receptor subunit composition at the synapse.
2009,
Pubmed
Altschul,
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
1997,
Pubmed
Amici,
Effects of the antibiotic gentamicin on nicotinic acetylcholine receptors.
2005,
Pubmed
,
Xenbase
Aubry,
Aspects of the pharmacology of a new anthelmintic: pyrantel.
1970,
Pubmed
Beech,
Nematode parasite genes: what's in a name?
2010,
Pubmed
Bendtsen,
Improved prediction of signal peptides: SignalP 3.0.
2004,
Pubmed
Boulin,
Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor.
2008,
Pubmed
,
Xenbase
Castresana,
Selection of conserved blocks from multiple alignments for their use in phylogenetic analysis.
2000,
Pubmed
Colquhoun,
The pharmacology of cholinoceptors on the somatic muscle cells of the parasitic nematode Ascaris suum.
1991,
Pubmed
Culetto,
The Caenorhabditis elegans unc-63 gene encodes a levamisole-sensitive nicotinic acetylcholine receptor alpha subunit.
2004,
Pubmed
Edgar,
MUSCLE: multiple sequence alignment with high accuracy and high throughput.
2004,
Pubmed
Eimer,
Regulation of nicotinic receptor trafficking by the transmembrane Golgi protein UNC-50.
2007,
Pubmed
Fauvin,
cDNA-AFLP analysis in levamisole-resistant Haemonchus contortus reveals alternative splicing in a nicotinic acetylcholine receptor subunit.
2010,
Pubmed
Fischer,
Trans-splicing in C. elegans generates the negative RNAi regulator ERI-6/7.
2008,
Pubmed
Fleming,
Caenorhabditis elegans levamisole resistance genes lev-1, unc-29, and unc-38 encode functional nicotinic acetylcholine receptor subunits.
1997,
Pubmed
,
Xenbase
Gottschalk,
Identification and characterization of novel nicotinic receptor-associated proteins in Caenorhabditis elegans.
2005,
Pubmed
Halevi,
The C. elegans ric-3 gene is required for maturation of nicotinic acetylcholine receptors.
2002,
Pubmed
,
Xenbase
Halevi,
Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression.
2003,
Pubmed
,
Xenbase
Haugstetter,
Identification and characterization of a novel thioredoxin-related transmembrane protein of the endoplasmic reticulum.
2005,
Pubmed
Hoekstra,
Characterization of an acetylcholine receptor gene of Haemonchus contortus in relation to levamisole resistance.
1997,
Pubmed
Jones,
The nicotinic acetylcholine receptor gene family of the nematode Caenorhabditis elegans: an update on nomenclature.
2007,
Pubmed
Jospin,
A neuronal acetylcholine receptor regulates the balance of muscle excitation and inhibition in Caenorhabditis elegans.
2009,
Pubmed
,
Xenbase
Kaplan,
Drug resistance in nematodes of veterinary importance: a status report.
2004,
Pubmed
Lewis,
The genetics of levamisole resistance in the nematode Caenorhabditis elegans.
1980,
Pubmed
Lewis,
Cholinergic receptor mutants of the nematode Caenorhabditis elegans.
1987,
Pubmed
Martin,
Oxantel is an N-type (methyridine and nicotine) agonist not an L-type (levamisole and pyrantel) agonist: classification of cholinergic anthelmintics in Ascaris.
2004,
Pubmed
Millar,
RIC-3: a nicotinic acetylcholine receptor chaperone.
2008,
Pubmed
Mitreva,
Comparative genomics of gene expression in the parasitic and free-living nematodes Strongyloides stercoralis and Caenorhabditis elegans.
2004,
Pubmed
Moreno-Guzmán,
Levamisole binding sites in Haemonchus contortus.
1998,
Pubmed
Neveu,
Genetic diversity of levamisole receptor subunits in parasitic nematode species and abbreviated transcripts associated with resistance.
2010,
Pubmed
Paoletti,
Glycine-independent and subunit-specific potentiation of NMDA responses by extracellular Mg2+.
1995,
Pubmed
,
Xenbase
Peter,
Haemonchus contortus: parasite problem No. 1 from tropics - Polar Circle. Problems and prospects for control based on epidemiology.
2005,
Pubmed
Qian,
Pharmacology of N-, L-, and B-subtypes of nematode nAChR resolved at the single-channel level in Ascaris suum.
2006,
Pubmed
Qian,
Levamisole resistance resolved at the single-channel level in Caenorhabditis elegans.
2008,
Pubmed
Rayes,
Activation of single nicotinic receptor channels from Caenorhabditis elegans muscle.
2007,
Pubmed
Richmond,
One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction.
1999,
Pubmed
Robertson,
Resistance to levamisole resolved at the single-channel level.
1999,
Pubmed
Roos,
Genetic analysis of inbreeding of two strains of the parasitic nematode Haemonchus contortus.
2004,
Pubmed
Sangster,
Investigation of the mechanism of levamisole resistance trichostrongylid nematodes of sheep.
1988,
Pubmed
Sangster,
Binding of [3H]m-aminolevamisole to receptors in levamisole-susceptible and -resistant Haemonchus contortus.
1998,
Pubmed
Schultz,
SMART, a simple modular architecture research tool: identification of signaling domains.
1998,
Pubmed
Sumikawa,
The amino acid residues 1-128 in the alpha subunit of the nicotinic acetylcholine receptor contain assembly signals.
1994,
Pubmed
,
Xenbase
Towers,
The Caenorhabditis elegans lev-8 gene encodes a novel type of nicotinic acetylcholine receptor alpha subunit.
2005,
Pubmed
Tyrrell,
Overcoming macrocyclic lactone resistance in Haemonchus contortus with pulse dosing of levamisole.
2010,
Pubmed
Verrall,
The N-terminal domains of acetylcholine receptor subunits contain recognition signals for the initial steps of receptor assembly.
1992,
Pubmed
Walker,
Cloning and structural analysis of partial acetylcholine receptor subunit genes from the parasitic nematode Teladorsagia circumcincta.
2001,
Pubmed
Wiley,
Cloning and sequence analysis of the candidate nicotinic acetylcholine receptor alpha subunit gene tar-1 from Trichostrongylus colubriformis.
1996,
Pubmed
Williamson,
The cys-loop ligand-gated ion channel gene family of Brugia malayi and Trichinella spiralis: a comparison with Caenorhabditis elegans.
2007,
Pubmed
Williamson,
The nicotinic acetylcholine receptors of the parasitic nematode Ascaris suum: formation of two distinct drug targets by varying the relative expression levels of two subunits.
2009,
Pubmed
,
Xenbase
