+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Effects of glutamate and ivermectin on single glutamate-gated chloride channels of the parasitic nematode H. contortus



Effects of glutamate and ivermectin on single glutamate-gated chloride channels of the parasitic nematode H. contortus



Plos Pathogens 13(10): E1006663



Ivermectin (IVM) is a widely-used anthelmintic that works by binding to and activating glutamate-gated chloride channel receptors (GluClRs) in nematodes. The resulting chloride flux inhibits the pharyngeal muscle cells and motor neurons of nematodes, causing death by paralysis or starvation. IVM resistance is an emerging problem in many pest species, necessitating the development of novel drugs. However, drug optimisation requires a quantitative understanding of GluClR activation and modulation mechanisms. Here we investigated the biophysical properties of homomeric α (avr-14b) GluClRs from the parasitic nematode, H. contortus, in the presence of glutamate and IVM. The receptor proved to be highly responsive to low nanomolar concentrations of both compounds. Analysis of single receptor activations demonstrated that the GluClR oscillates between multiple functional states upon the binding of either ligand. The G36'A mutation in the third transmembrane domain, which was previously thought to hinder access of IVM to its binding site, was found to decrease the duration of active periods and increase receptor desensitisation. On an ensemble macropatch level the mutation gave rise to enhanced current decay and desensitisation rates. Because these responses were common to both glutamate and IVM, and were observed under conditions where agonist binding sites were likely saturated, we infer that G36'A affects the intrinsic properties of the receptor with no specific effect on IVM binding mechanisms. These unexpected results provide new insights into the activation and modulatory mechanisms of the H. contortus GluClRs and provide a mechanistic framework upon which the actions of drugs can be reliably interpreted.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 059660080

Download citation: RISBibTeXText

PMID: 28968469

DOI: 10.1371/journal.ppat.1006663


Related references

An ivermectin-sensitive glutamate-gated chloride channel from the parasitic nematode Haemonchus contortus. Molecular Pharmacology 75(6): 1347-1355, 2009

Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans. Plos one 6(7): E22390, 2011

Distribution of glutamate-gated chloride channel subunits in the parasitic nematode Haemonchus contortus. Journal of Comparative Neurology 462(2): 213-222, 2003

Ivermectin binds to recombinant nematode glutamate-gated chloride channels with high affinity. European Journal of Neuroscience 12(Suppl. 11): 44, 2000

Cloning, sequencing, and developmental expression levels of a novel glutamate-gated chloride channel homologue in the parasitic nematode Haemonchus contortus. Biochemical and Biophysical Research Communications 254(3): 529-534, 1999

High-affinity ivermectin binding to recombinant subunits of the Haemonchus contortus glutamate-gated chloride channel. Molecular and Biochemical Parasitology 114(2): 161-168, 2001

Haemonchus contortus: selection at a glutamate-gated chloride channel gene in ivermectin- and moxidectin-selected strains. Experimental Parasitology 90(1): 42-48, 1998

Ivermectin binds to GABA and glutamate-gated chloride channels in Drosophila melanogaster. Society for Neuroscience Abstracts 25(1-2): 1484, 1999

Synthesis of photoreactive ivermectin B1a derivatives and their actions on Haemonchus and Bombyx glutamate-gated chloride channels. Pesticide Biochemistry and Physiology 120: 82-90, 2015

Subunit determinants of the pharmacological properties of glutamate and ivermectin-gated chloride channels in Caenorhabditis elegans. European Journal of Neuroscience 12(Suppl. 11): 451, 2000

Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin. Proceedings of the National Academy of Sciences of the United States of America 97(25): 13949-13954, 2000

Glutamate-Gated Chloride Channels In Caenorhabditis elegans And Parasitic Nematodes. Biochemical Society Transactions 25(3): 535S.5-535S, 1997

Cloning and heterologous expression of glutamate-gated chloride channels from fleas High affinity activation by ivermectin phosphate. Biophysical Journal 74(2 Part 2): A386, 1998

Dorsal unpaired median neurons of locusta migratoria express ivermectin- and fipronil-sensitive glutamate-gated chloride channels. Journal of Neurophysiology 97(4): 2642-2650, 2007

Amino acid residues of both the extracellular and transmembrane domains influence binding of the antiparasitic agent milbemycin to Haemonchus contortus AVR-14B glutamate-gated chloride channels. Biochemical and Biophysical Research Communications 419(3): 562-566, 2012