Skip to main content
×
Home
    • Aa
    • Aa

Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics

  • A. J. WOLSTENHOLME (a1) and A. T. ROGERS (a1)
Abstract

The macrocyclic lactones are the biggest selling and arguably most effective anthelmintics currently available. They are good substrates for the P-glycoproteins, which might explain their selective toxicity for parasites over their vertebrate hosts. Changes in the expression of these pumps have been implicated in resistance to the macrocyclic lactones, but it is clear that they exert their anthelmintic effects by binding to glutamate-gated chloride channels expressed on nematode neurones and pharyngeal muscle cells. This effect is quite distinct from the channel opening induced by glutamate, the endogenous transmitter acting at these receptors, which produces rapidly opening and desensitising channels. Ivermectin-activated channels open very slowly but essentially irreversibly, leading to a very long-lasting hyperpolarisation or depolarisation of the neurone or muscle cell and therefore blocking further function. Molecular and genetic studies have shown that there are multiple GluCl isoforms in both free-living and parasitic nematodes: the exact genetic make-up and functions of the GluCl may vary between species. The known expression patterns of the GluCl explain most of the observed biological effects of treatment with the macrocyclic lactones, though the reason for the long-lasting inhibition of larval production in filarial species is still poorly understood.

Copyright
Corresponding author
Tel: 01225 386553. Fax: 01225 386779. E-mail: A.J.Wolstenholme@bath.ac.uk
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

ADELSBERGER, H., SCHEUR, T. & DUDEL, J. ( 1997). A patch clamp study of a glutamate chloride channel on pharyngeal muscle of the nematode Ascaris suum. Neuroscience Letters230, 183186.

ANZIANI, O. S., ZIMMERMANN, G., GUGLIEMONE, A. A., VAZQUEZ, R. & SUAREZ, E. ( 2001). Avermectin resistance in Cooperia pectinata in cattle in Argentina. Veterinary Record149, 5859.

ARENA, J. P., LIU, K. K., PARESS, P. S. & CULLY, D. F. ( 1992). Expression of a glutamate-activated chloride current in Xenopus oocytes injected with Caenorhabditis elegans RNA: evidence for modulation by avermectin. Molecular Brain Research15, 339348.

ARENA, J. P., LIU, K. K., PARESS, P. S., FRAZIER, E. G., CULLY, D. F., MROZIK, H. & SCHAEFFER, J. M. ( 1995). The mechanism of action of avermectins in Caenorhabditis elegans – correlation between activation of glutamate-sensitive chloride current, membrane-binding and biological-activity. Journal of Parasitology81, 286294.

AVERY, L. & HORVITZ, H. R. ( 1990). Effects of starvation and neuroactive drugs on feeding in Caenorhabditis elegans. Journal of Experimental Zoology253, 263270.

BLACKHALL, W. J., LIU, H. Y., XU, M., PRICHARD, R. K. & BEECH, R. N. ( 1998). Selection at a P-glycoprotein gene in ivermectin- and moxidectin-selected strains of Haemonchus contortus. Molecular and Biochemical Parasitology95, 193201.

BOTTJER, K. P. & BONE, L. W. ( 1985). Trichostrongylus colubriformis: effect of anthelmintics on ingestion and oviposition. International Journal for Parasitology15, 501503.

BROCKIE, P. J., MELLEM, J. E., HILLS, T., MADSEN, T. M. & MARICQ, A. V. ( 2001). The C. elegans glutamate receptor subunit NMR-1 is required for slow NMDA-activated currents that regulate reversal frequency during locomotion. Neuron31, 617630.

BROWNLEE, D. A., HOLDEN-DYE, L. & WALKER, R. J. ( 1997). Actions of the anthelmintic ivermectin on the pharyngeal muscle of the parasitic nematode Ascaris suum. Parasitology115, 553561.

CAMPBELL, W. C., FISHER, M. H., STAPLEY, E. O., ALBERS-SCHÖNBERG, G. & JACOB, T. A. ( 1983). Ivermectin: a potent new antiparasitic agent. Science221, 823828.

CASCIO, M. ( 2004). Structure and function of the glycine receptor and related nicotinicoid receptors. Journal of Biological Chemistry279, 1938319386.

CHEESEMAN, C. L., DELANY, N. S., WOODS, D. J. & WOLSTENHOLME, A. J. ( 2001). High-affinity ivermectin binding to recombinant subunits of the Haemonchus contortus glutamate-gated chloride channel. Molecular and Biochemical Parasitology114, 161168.

CULLY, D. F., VASSILATIS, D. K., LIU, K. K., PARESS, P., VAN DER PLOEG, L. H. T., SCHAEFFER, J. M. & ARENA, J. P. ( 1994). Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature, London371, 707711.

DELANY, N. S., LAUGHTON, D. L. & WOLSTENHOLME, A. J. ( 1998). Cloning and localisation of an avermectin receptor-related subunit from Haemonchus contortus. Molecular and Biochemical Parasitology97, 177187.

DENT, J. A., DAVIS, M. W. & AVERY, L. ( 1997). avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans. EMBO Journal16, 58675879.

DENT, J. A., SMITH, M. M., VASSILATIS, D. K. & AVERY, L. ( 2000). The genetics of avermectin resistance in Caenorhabditis elegans. Proceedings of the National Academy of Sciences, USA97, 26742679.

DROGEMULLER, M., SCHNIEDER, T. & VON SAMSON-HIMMELSTJERNA, G. ( 2004). Evidence of P-glycoprotein sequence diversity in cyathostomins. Journal of Parasitology90, 9981003.

ETTER, A., CULLY, D. F., SCHAEFFER, J. M., LIU, K. K. & ARENA, J. P. ( 1996). An amino acid substitution in the pore region of a glutamate gated chloride channel enables the coupling of ligand binding to channel gating. Journal of Biological Chemistry271, 1603516039.

FENG, X.-P., HAYASHI, P., BEECH, R. N. & PRICHARD, R. K. ( 2002). Study of the nematode putative GABA type-A receptor subunits: evidence for modulation by ivermectin. Journal of Neurochemistry83, 870878.

FIRE, A., HARRISON, S. W. & DIXON, D. ( 1990). A modular set of LacZ fusion vectors for studying gene expression in Caenorhabditis elegans. Gene93, 189198.

FORRESTER, S. G., BEECH, R. N. & PRICHARD, R. K. ( 2004). Agonist enhancement of macrocyclic lactone activity at a glutamate-gated chloride channel subunit from Haemonchus contortus. Biochemical Pharmacology67, 10191024.

FORRESTER, S. G., HAMDAN, F. F., PRICHARD, R. K. & BEECH, R. N. ( 1999). Cloning, sequencing, and developmental expression levels of a novel glutamate-gated chloride channel homologue in the parasitic nematode Haemonchus contortus. Biochemical and Biophysical Research Communications254, 529534.

FORRESTER, S. G., PRICHARD, R. K. & BEECH, R. N. ( 2002). A glutamate-gated chloride channel subunit from Haemonchus contortus: Expression in a mammalian cell line, ligand binding, and modulation of anthelmintic binding by glutamate. Biochemical Pharmacology63, 10611068.

FORRESTER, S. G., PRICHARD, R. K., DENT, J. A. & BEECH, R. N. ( 2003). Haemonchus contortus: HcGluCla expressed in Xenopus oocytes forms a glutamate-gated ion channel that is activated by ibotenate and the antiparasitic drug ivermectin. Molecular and Biochemical Parasitology129, 115121.

FREEMAN, A. S., NGHIEM, C., LI, J., ASHTON, F. T., GUERRERO, J., SHOOP, W. L. & SCHAD, G. A. ( 2003). Amphidial structure of ivermectin-resistant and susceptible laboratory and field strains of Haemonchus contortus. Veterinary Parasitology110, 217226.

GEARY, T. G., SIMS, S. M., THOMAS, E. M., VANOVER, L., DAVIS, J. P., WINTEROWD, C. A., KLEIN, R., NORMAN, H. O. & THOMPSON, J. P. ( 1993). Haemonchus contortus: Ivermectin-induced paralysis of the pharynx. Experimental Parasitology77, 8896.

GILL, J. H., REDWIN, J. M., VAN WYK, J. A. & LACEY, E. ( 1995). Avermectin inhibition of larval development in Haemonchus contortus – Effects of ivermectin resistance. International Journal for Parasitology25, 463470.

GRAHAM, D., PFEIFFER, F. & BETZ, H. ( 1982). Avermectin B1a inhibits the binding of strychnine to the glycine receptor of rat spinal-cord. Neuroscience Letters29, 173176.

HEJMADI, M. V., JAGANNATHAN, S., DELANY, N. S., COLES, G. C. & WOLSTENHOLME, A. J. ( 2000). L-glutamate binding sites of parasitic nematodes: an association with ivermectin resistance? Parasitology120, 535545.

HOLDEN-DYE, L., HEWITT, G. M., WANN, K. T., KROGSGAARDLARSEN, P. & WALKER, R. J. ( 1988). Studies involving avermectin and the 4-aminobutyric acid (GABA) receptor of Ascaris suum muscle. Pesticide Science24, 231245.

HOROSZOK, L., RAYMOND, V., SATTELLE, D. B. & WOLSTENHOLME, A. J. ( 2001). GLC-3: a novel fipronil and BIDN-sensitive, but picrotoxinin-insensitive, L-glutamate-gated chloride channel subunit from Caenorhabditis elegans. British Journal of Pharmacology132, 12471254.

JACKSON, F. & COOP, R. L. ( 2000). The development of anthelmintic resistance in sheep nematodes. Parasitology120, S95S107.

JAGANNATHAN, S., LAUGHTON, D. L., CRITTEN, C. L., SKINNER, T. M., HOROSZOK, L. & WOLSTENHOLME, A. J. ( 1999). Ligand-gated chloride channel subunits encoded by the Haemonchus contortus and Ascaris suum orthologues of the Caenorhabditis elegans gbr-2 (avr-14) gene. Molecular and Biochemical Parasitology103, 129140.

KAPLAN, R. M. ( 2004). Drug resistance in nematodes of veterinary importance: a status report. Trends in Parasitology20, 477481.

KASS, I. S., STRETTON, A. O. W. & WANG, C. C. ( 1984). The effects of avermectin and drugs related to acetylcholine and 4-aminobutyric acid on neurotransmitters in Ascaris suum. Molecular and Biochemical Parasitology13, 213225.

KASS, I. S., WANG, C. C., WALROW, J. P. & STRETTON, A. O. W. ( 1980). Avermectin b1A, a paralysing anthelmintic that affects interneurons and inhibitory motorneurons in Ascaris. Proceedings of the National Academy of Sciences, USA77, 62116215.

KERBOEUF, D., BLACKHALL, W. J., KAMINSKY, R. & VON samson-himmelstjerna, G. ( 2003). P-glycoprotein in helminths: function and perspectives for anthelmintic treatment and reversal of resistance. International Journal of Antimicrobial Agents22, 322346.

LAUGHTON, D. L., LUNT, G. G. & WOLSTENHOLME, A. J. ( 1997b). Alternative splicing of a Caenorhabditis elegans gene produces two novel inhibitory amino acid receptor subunits with identical ligand-binding domains but different ion channels. Gene201, 119125.

LOVERIDGE, B., McARTHUR, M., McKENNA, P. & MARIADASS, B. ( 2003). Probable multigeneric resistance to macrocyclic lactone anthelmintics in cattle in New Zealand. New Zealand Veterinary Journal51, 139141.

MARTIN, R. J. & PENNINGTON, A. J. ( 1989). A patch-clamp study of effects of dihydroavermectin on Ascaris muscle. British Journal of Pharmacology98, 747756.

McINTIRE, S. L., JORGENSEN, E. M., KAPLAN, J. & HORVITZ, H. R. ( 1993). The GABAergic nervous system of Caenorhabditis elegans. Nature, London364, 337341.

MEALEY, K. L., BENTJEN, S. A., GAY, J. M. & CANTOR, G. H. ( 2001). Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics11, 727733.

MELLEM, J. E., BROCKIE, P. J., ZHENG, Y., MADSEN, D. M. & MARICQ, A. V. ( 2002). Decoding of polymodal sensory stimuli by postsynaptic glutamate receptors in C. elegans. Neuron36, 933944.

MES, T. H. M. ( 2004). Purifying selection and demographic expansion affect sequence diversity of the ligand-binding domain of a glutamate-gated chloride channel gene of Haemonchus placei. Journal of Molecular Evolution58, 466478.

NJUE, A. I., HAYASHI, J., KINNE, J., FENG, X.-P. & PRICHARD, R. K. ( 2004). Mutations in the extracellular domain of glutamate-gated chloride channel α3 and β subunits from ivermectin-resistant Cooperia oncophora affect agonist sensitivity. Journal of Neurochemistry89, 11371147.

NOBMANN, S., BAUER, B. & FRICKER, G. ( 2001). Ivermectin excretion by isolated functionally intact brain endothelial capillaries. British Journal of Pharmacology132, 722728.

OMURA, S. & CRUMP, A. ( 2004). The life and times of ivermectin – A success story. Nature Reviews Microbiology2, 984989.

PAIEMENT, J.-P., LEGER, C., RIBEIRO, P. & PRICHARD, R. K. ( 1999). Haemonchus contortus: effects of glutamate, ivermectin, and moxidectin on inulin uptake activity in unselected and ivermectin-selected adults. Experimental Parasitology92, 193198.

PERRY, R. N. ( 2001). Analysis of the sensory responses of parasitic nematodes using electrophysiology. International Journal for Parasitology31, 909918.

PETERSEN, M. B., VARADY, M., BJORN, H. & NANSEN, P. ( 1996). Efficacies of different doses of ivermectin against male, female and L4 Oesophagostomum dentatum in pigs. Veterinary Parasitology65, 5563.

PONG, S. S. & WANG, C. C. ( 1982). Avermectin-B1a modulation of gamma-aminobutyric acid receptors in rat-brain membranes. Journal of Neurochemistry38, 375379.

PORTILLO, V., JAGANNATHAN, S. & WOLSTENHOLME, A. J. ( 2003). Distribution of glutamate-gated chloride channel subunits in the parasitic nematode Haemonchus contortus. Journal of Comparative Neurology462, 213222.

RAIZEN, D. M. & AVERY, L. ( 1994). Electrical activity and behaviour in the pharynx of Caenorhabditis elegans. Neuron12, 483495.

ROLFE, R. N., BARRETT, J. & PERRY, R. N. ( 2001). Electrophysiological analysis of responses of adult females of Brugia pahangi to some chemicals. Parasitology122, 347357.

ROULET, A., PUEL, O., GESTA, S., LEPAGE, J. F., DRAG, M., SOLL, M., ALVINERIE, M. & PINEAU, T. ( 2003). MDR1-deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin. European Journal of Pharmacology460, 8591.

SANGSTER, N. C., BANNAN, S. C., WEISS, A. S., NULF, S. C., KLEIN, R. D. & GEARY, T. G. ( 1999). Haemonchus contortus: Sequence heterogeneity of internucleotide binding domains from P-glycoproteins and an association with avermectin/milbemycin resistance. Experimental Parasitology91, 250257.

SHAN, Q., HADDRILL, J. L. & LYNCH, J. W. ( 2001). Ivermectin, an unconventional agonist of the glycine receptor chloride channel. Journal of Biological Chemistry276, 1255612564.

SUPAVILAI, P. & KAROBATH, M. ( 1981). In vitro modulation by avermectin-B1a of the GABA-benzodiazepine receptor complex of rat cerebellum. Journal of Neurochemistry36, 798803.

VASSILATIS, D. K., ARENA, J. P., PLASTERK, R. H. A., WILKINSON, H., SCHAEFFER, J. M., CULLY, D. F. & VAN der ploeg, L. H. T. ( 1997a). Genetic and biochemical evidence for a novel avermectin sensitive chloride channel in C. elegans: isolation and characterisation. Journal of Biological Chemistry272, 3316733174.

VASSILATIS, D. K., ELLISTON, K., PARESS, P. S., HAMELIN, M., ARENA, J. P., SCHAEFFER, J. M., VAN der ploeg, L. H. T. & CULLY, D. F. ( 1997b). Evolutionary relationship of the ligand-gated ion channels and the avermectin sensitive, glutamate-gated chloride channels. Journal of Molecular Evolution44, 501508.

VERCRUYSSE, J. & REW, R. E. ( 2002). Macrocyclic Lactones in Antiparasitic Therapy. CABI Publishing, Wallingford, UK.

WHITE, J. G., SOUTHGATE, E., THOMPSON, J. N. & BRENNER, S. ( 1986). The structure of the nervous system of Caenorhabditis elegans. Philosophical Transactions of the Royal Society of London Series B314, 1340.

WOLSTENHOLME, A. J., FAIRWEATHER, I., PRICHARD, R. K., VON SAMSON-HIMMELSTJERNA, G. & SANGSTER, N. C. ( 2004). Drug resistance in veterinary helminths. Trends in Parasitology20, 469476.

YATES, D. M., PORTILLO, V. & WOLSTENHOLME, A. J. ( 2003). The avermectin receptors of Haemonchus contortus and Caenorhabditis elegans. International Journal for Parasitology33, 11831193.

YATES, D. M. & WOLSTENHOLME, A. J. ( 2004). An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis. International Journal for Parasitology34, 10651071.

ZHENG, Y., BROCKIE, P. J., MELLEM, J. E., MADSEN, D. M. & MARICQ, A. V. ( 1999). Neuronal control of locomotion in C. elegans is modified by a dominant mutation in the GLR-1 ionotropic glutamate receptor. Neuron24, 347361.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Parasitology
  • ISSN: 0031-1820
  • EISSN: 1469-8161
  • URL: /core/journals/parasitology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords: