Recent Progress in Understanding the Interaction Between Avermectins and Ligand-gated Ion Channels: Putting the Pests to Sleep

Overview

Journal Invert Neurosci

Date 2010 Oct 19

PMID 20953673

Citations 10

Authors

Adrian J Wolstenholme

Affiliations

Soon will be listed here.

Abstract

Avermectins and milbemycins are an important family of anthelmintics, insecticides and acaricides. Their mode of action is as positive allosteric modulators of ligand-gated chloride channels, and at higher concentrations, they gate some channels directly. Though it has long been known that the avermectins do not compete for the ligand binding site, the actual site at which they interact with their receptors has been unclear. Recent data demonstrate the importance to drug binding of amino acid residues predicted to line a water-filled pocket in the channel domain. This pocket acts as the binding site for anaesthetics and other modulators of mammalian GABA(A) and glycine receptors, suggesting similarities in the mode of action between these drugs and the avermectins/milbemycins.

Citing Articles

Apoptosis-Inducing and Proliferation-Inhibiting Effects of Doramectin on Mz-ChA-1 Human Cholangiocarcinoma Cells.

Zhang Y, Wu W, Shi Y, Huang Y, Dai T, Ke L Int J Mol Sci. 2025; 25(24.

PMID: 39769205 PMC: 11676298. DOI: 10.3390/ijms252413440.

The relative contribution of target-site mutations in complex acaricide resistant phenotypes as assessed by marker assisted backcrossing in Tetranychus urticae.

Riga M, Bajda S, Themistokleous C, Papadaki S, Palzewicz M, Dermauw W Sci Rep. 2017; 7(1):9202.

PMID: 28835683 PMC: 5569037. DOI: 10.1038/s41598-017-09054-y.

Signaling in Parasitic Nematodes: Physicochemical Communication Between Host and Parasite and Endogenous Molecular Transduction Pathways Governing Worm Development and Survival.

Lok J Curr Clin Microbiol Rep. 2017; 3(4):186-197.

PMID: 28781934 PMC: 5543980. DOI: 10.1007/s40588-016-0046-2.

Maternal inheritance of deltamethrin resistance in the salmon louse Lepeophtheirus salmonis (Krøyer) is associated with unique mtDNA haplotypes.

Carmona-Antonanzas G, Bekaert M, Humble J, Boyd S, Roy W, Bassett D PLoS One. 2017; 12(7):e0180625.

PMID: 28704444 PMC: 5507548. DOI: 10.1371/journal.pone.0180625.

Impaired Recall of Positional Memory following Chemogenetic Disruption of Place Field Stability.

Zhao R, Grunke S, Keralapurath M, Yetman M, Lam A, Lee T Cell Rep. 2016; 16(3):793-804.

PMID: 27373150 PMC: 4956499. DOI: 10.1016/j.celrep.2016.06.032.

References

Rohrer S, Evans D, Bergstrom A . A membrane associated glutamate binding protein from Caenorhabditis elegans and Haemonchus contortus. Comp Biochem Physiol C Comp Pharmacol Toxicol. 1990; 95(2):223-8. DOI: 10.1016/0742-8413(90)90108-l. View

Kane N, HIRSCHBERG B, Qian S, Hunt D, Thomas B, Brochu R . Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin. Proc Natl Acad Sci U S A. 2000; 97(25):13949-54. PMC: 17681. DOI: 10.1073/pnas.240464697. View

Collins T, Millar N . Nicotinic acetylcholine receptor transmembrane mutations convert ivermectin from a positive to a negative allosteric modulator. Mol Pharmacol. 2010; 78(2):198-204. PMC: 2917854. DOI: 10.1124/mol.110.064295. View

Unwin N . Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol. 2005; 346(4):967-89. DOI: 10.1016/j.jmb.2004.12.031. View

Cully D, Vassilatis D, Liu K, Paress P, Van der Ploeg L, Schaeffer J . Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature. 1994; 371(6499):707-11. DOI: 10.1038/371707a0. View

Khakh B, Proctor W, Dunwiddie T, Labarca C, Lester H . Allosteric control of gating and kinetics at P2X(4) receptor channels. J Neurosci. 1999; 19(17):7289-99. PMC: 6782529. View

Bertrand D, Bertrand S, Cassar S, Gubbins E, Li J, Gopalakrishnan M . Positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor: ligand interactions with distinct binding sites and evidence for a prominent role of the M2-M3 segment. Mol Pharmacol. 2008; 74(5):1407-16. DOI: 10.1124/mol.107.042820. View

Hejmadi M, Jagannathan S, Delany N, Coles G, Wolstenholme A . L-glutamate binding sites of parasitic nematodes: an association with ivermectin resistance?. Parasitology. 2000; 120 ( Pt 5):535-45. DOI: 10.1017/s0031182099005843. View

Kwon D, Yoon K, Clark J, Lee S . A point mutation in a glutamate-gated chloride channel confers abamectin resistance in the two-spotted spider mite, Tetranychus urticae Koch. Insect Mol Biol. 2010; 19(4):583-91. DOI: 10.1111/j.1365-2583.2010.01017.x. View

10.

Browne L, Jiang L, North R . New structure enlivens interest in P2X receptors. Trends Pharmacol Sci. 2010; 31(5):229-37. PMC: 2954318. DOI: 10.1016/j.tips.2010.02.004. View

11.

Raymond V, Mongan N, Sattelle D . Anthelmintic actions on homomer-forming nicotinic acetylcholine receptor subunits: chicken alpha7 and ACR-16 from the nematode Caenorhabditis elegans. Neuroscience. 2000; 101(3):785-91. DOI: 10.1016/s0306-4522(00)00279-7. View

12.

Dent J, Smith M, Vassilatis D, Avery L . The genetics of ivermectin resistance in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2000; 97(6):2674-9. PMC: 15988. DOI: 10.1073/pnas.97.6.2674. View

13.

Kehoe J, Buldakova S, Acher F, Dent J, Bregestovski P, Bradley J . Aplysia cys-loop glutamate-gated chloride channels reveal convergent evolution of ligand specificity. J Mol Evol. 2009; 69(2):125-41. DOI: 10.1007/s00239-009-9256-z. View

14.

Jelinkova I, Vavra V, Jindrichova M, Obsil T, Zemkova H, Zemkova H . Identification of P2X(4) receptor transmembrane residues contributing to channel gating and interaction with ivermectin. Pflugers Arch. 2008; 456(5):939-50. DOI: 10.1007/s00424-008-0450-4. View

15.

Wolstenholme A, Rogers A . Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics. Parasitology. 2006; 131 Suppl:S85-95. DOI: 10.1017/S0031182005008218. View

16.

Bertrand D, Bertrand S, BALLIVET M . Pharmacological properties of the homomeric alpha 7 receptor. Neurosci Lett. 1992; 146(1):87-90. DOI: 10.1016/0304-3940(92)90179-b. View

17.

Serafini R, Bracamontes J, Steinbach J . Structural domains of the human GABAA receptor 3 subunit involved in the actions of pentobarbital. J Physiol. 2000; 524 Pt 3:649-76. PMC: 2269912. DOI: 10.1111/j.1469-7793.2000.00649.x. View

18.

McCavera S, Rogers A, Yates D, Woods D, Wolstenholme A . An ivermectin-sensitive glutamate-gated chloride channel from the parasitic nematode Haemonchus contortus. Mol Pharmacol. 2009; 75(6):1347-55. PMC: 2684884. DOI: 10.1124/mol.108.053363. View

19.

Rohrer S, Birzin E, Eary C, Schaeffer J, Shoop W . Ivermectin binding sites in sensitive and resistant Haemonchus contortus. J Parasitol. 1994; 80(3):493-7. View

20.

Shan Q, Haddrill J, Lynch J . Ivermectin, an unconventional agonist of the glycine receptor chloride channel. J Biol Chem. 2001; 276(16):12556-64. DOI: 10.1074/jbc.M011264200. View