GluClR-mediated inhibitory postsynaptic currents reveal targets for ivermectin and potential mechanisms of ivermectin resistance.
Animals
Chloride Channels
/ antagonists & inhibitors
Excitatory Amino Acid Antagonists
/ metabolism
Glutamic Acid
/ pharmacology
HEK293 Cells
Haemonchus
/ drug effects
Humans
Inhibitory Postsynaptic Potentials
/ drug effects
Ivermectin
/ pharmacology
Patch-Clamp Techniques
/ methods
Receptors, Glutamate
/ metabolism
Xenopus laevis
/ embryology
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
04
10
2018
accepted:
08
01
2019
revised:
08
02
2019
pubmed:
30
1
2019
medline:
19
3
2019
entrez:
30
1
2019
Statut:
epublish
Résumé
Glutamate-gated chloride channel receptors (GluClRs) mediate inhibitory neurotransmission at invertebrate synapses and are primary targets of parasites that impact drastically on agriculture and human health. Ivermectin (IVM) is a broad-spectrum pesticide that binds and potentiates GluClR activity. Resistance to IVM is a major economic and health concern, but the molecular and synaptic mechanisms of resistance are ill-defined. Here we focus on GluClRs of the agricultural endoparasite, Haemonchus contortus. We demonstrate that IVM potentiates inhibitory input by inducing a tonic current that plateaus over 15 minutes and by enhancing post-synaptic current peak amplitude and decay times. We further demonstrate that IVM greatly enhances the active durations of single receptors. These effects are greatly attenuated when endogenous IVM-insensitive subunits are incorporated into GluClRs, suggesting a mechanism of IVM resistance that does not affect glutamate sensitivity. We discovered functional groups of IVM that contribute to tuning its potency at different isoforms and show that the dominant mode of access of IVM is via the cell membrane to the receptor.
Identifiants
pubmed: 30695069
doi: 10.1371/journal.ppat.1007570
pii: PPATHOGENS-D-18-01918
pmc: PMC6368337
doi:
Substances chimiques
Chloride Channels
0
Excitatory Amino Acid Antagonists
0
Receptors, Glutamate
0
glutamate-gated chloride channels
0
Glutamic Acid
3KX376GY7L
Ivermectin
70288-86-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1007570Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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