Structural mechanism underlying the differential effects of ivermectin and moxidectin on the C. elegans glutamate-gated chloride channel GLC-2

Kaji, Mark D.; Noonan, Jennifer D.; Geary, Timothy G.; Beech, Robin N.

doi:10.1016/J.BIOPHA.2021.112380

Title

Structural mechanism underlying the differential effects of ivermectin and moxidectin on the C. elegans glutamate-gated chloride channel GLC-2

Author

Kaji, Mark D.

Noonan, Jennifer D.

Geary, Timothy G.

Beech, Robin N.

Abstract

Background and purpose Nematode glutamate-gated chloride channels (GluCls) are targets of ivermectin (IVM) and moxidectin (MOX), structurally dissimilar macrocyclic lactone (ML) anthelmintics. IVM and MOX possess different pharmacokinetics and efficacy profiles but are thought to have the same binding site, through which they allosterically activate GluCls, apart from the GLC-2 receptor, which is antagonized by IVM. Our goal was to determine GLC-2 sensitivity to MOX, investigate residues involved in antagonism of GLC-2, and to identify differences in receptor-level pharmacology between IVM and MOX. Experimental approach Two-electrode voltage clamp electrophysiology was used to study the pharmacology of Caenorhabditis elegans GLC-2 receptors heterologously expressed in Xenopus laevis oocytes. In silico homology modeling identified Cel-GLC-2 residues Met291 and Gln292 at the IVM binding site that differ from other GluCls; we mutated these residues to those found in ML-sensitive GluCls, and those of filarial nematode GLC-2. Key results We discovered that MOX inhibits wild-type C. elegans GLC-2 receptors roughly 10-fold more potently than IVM, and with greater maximal inhibition of glutamate activation (MOX = 86.9 ± 2.5%; IVM = 57.8 ± 5.9%). IVM was converted into an agonist in the Met291Gln mutant, but MOX remained an antagonist. Glutamate responses were abrogated in a Met291Leu Gln292Thr double mutant (mimicking filarial nematode GLC-2), but MOX and IVM were converted into positive allosteric modulators of glutamate at this construct. Conclusions and implications Our data provides new insights into differences in receptor-level pharmacology between IVM and MOX and identify residues responsible for ML antagonism of GLC-2.

Language

English

Source (journal)

Biomedicine and pharmacotherapy. - Poitiers, 1982, currens

Publication

Poitiers : 2022

ISSN

0753-3322

DOI

10.1016/J.BIOPHA.2021.112380

Volume/pages

145 (2022) , p. 1-12