8.C.5 The Ivermectin (IVM) Family
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. The IVM binding site in the Caenorhabditis elegans GluCl was identified by X-ray crystallographic analysis. Fuse et al. 2016 examined the action of IVM on the housefly (Musca domestica) GluCl and gamma-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 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 (Fuse et al. 2016).