Electrophysiological characterization of ivermectin triple actions on Musca chloride channels gated by l-glutamic acid and γ-aminobutyric acid

• Ivermectin (IVM) alone elicits inward currents in Musca chloride channels gated by glutamate (GluCls) and GABA.
• IVM potentiates currents induced by the EC5s of agonists in both channels.
• IVM inhibits currents induced by the EC90s of agonists in both channels.
• Substitution of a Gly in TM3 results in a significant reduction or loss of sensitivity to these actions exerted by IVM.
• GluCls are the primary target, judging by their high sensitivity to IVM actions.

Ivermectin (IVM) is a macrocyclic lactone that exerts antifilarial, antiparasitic, and insecticidal effects on nematodes and insects by acting on l-glutamic acid-gated chloride channels (GluCls). IVM also acts as an allosteric modulator of various other ion channels. Although the IVM binding site in the Caenorhabditis elegans GluCl was identified by X-ray crystallographic analysis, the mechanism of action of IVM in insects is not well defined. We therefore examined the action of IVM on the housefly (Musca domestica) GluCl and γ-aminobutyric acid (GABA)-gated ion channel (GABACl). For both channels, IVM induced currents by itself, potentiated currents induced by low concentrations of agonists, and inhibited currents induced by high concentrations of agonists. Despite exerting common actions on both types of channels, GluCls were more susceptible to IVM actions than GABACls, indicating that GluCls are the primary target of IVM. Substitution of an amino acid residue in the third transmembrane segment (G312M in GluCls, and G333A and G333M in GABACls) resulted in significantly reduced levels or loss of activation, potentiation, and antagonism of the channels, indicating that these three actions result from the interaction of IVM with amino acid residues in the transmembrane intersubunit crevice.

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