Research Article: GluClR-mediated inhibitory postsynaptic currents reveal targets for ivermectin and potential mechanisms of ivermectin resistance

Date Published: January 29, 2019

Publisher: Public Library of Science

Author(s): Mohammed Atif, Jennifer J. Smith, Argel Estrada-Mondragon, Xue Xiao, Angela A. Salim, Robert J. Capon, Joseph W. Lynch, Angelo Keramidas, Adrian J. Wolstenholme.

http://doi.org/10.1371/journal.ppat.1007570

Abstract

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.

Partial Text

Glutamate-gated chloride channel receptors (GluClRs) are a major class of pentameric ligand gated ion channels (pLGICs) [1] that mediate neuronal and muscular inhibition [2, 3]. They are expressed exclusively in invertebrates, making them ideal targets for the development of pesticides with minimal risk of unwanted activity at vertebrate pLGICs. GluClRs are of interest because they are an excellent model for understanding pLGIC structure at high resolution [4, 5], function and pharmacology [6, 7], and because many invertebrates that express them are commercially important pest species in agriculture [8–10], aquaculture [11] and in veterinary and human health [12].

Resistance to IVM in pest species is a growing problem worldwide. Previous research efforts have identified mutations and allelles of GluClRs associated with resistance to IVM, however, there is a lack of information regarding the mechanisms that underlie resistance. In this study, we investigated the synaptic and biophysical properties of different GluClR subtypes and detailed a possible mode of resistance in the pest species H. contortus.

 

Source:

http://doi.org/10.1371/journal.ppat.1007570

 

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