Ivermectin, an Unconventional Agonist of the Glycine Receptor Chloride Channel

Abstract

The effects of the antihelmintic, ivermectin, were investigated in recombinantly expressed human ␣ 1 homomeric and ␣ 1 ␤ heteromeric glycine receptors (GlyRs). At low (0.03 M) concentrations ivermectin potentiated the response to sub-saturating glycine concentrations, and at higher (>0.03 M) concentrations it irreversibly activated both ␣ 1 homomeric and ␣ 1 ␤ heteromeric GlyRs. Relative to glycine-gated currents, ivermectin-gated currents exhibited a dramatically reduced sensitivity to inhibition by strychnine, picrotoxin, and zinc. The insensitivity to strychnine could not be explained by ivermectin preventing the access of strychnine to its binding site. Furthermore, the elimination of a known glycine-and strychnine-binding site by site-directed mutagenesis had little effect on ivermectin sensitivity, demonstrating that the ivermectin-and glycine-binding sites were not identical. Ivermectin strongly and irreversibly activated a fast-desensitizing mutant GlyR after it had been completely desensitized by a saturating concentration of glycine. Finally, a mutation known to impair dramatically the glycine signal transduction mechanism had little effect on the apparent affinity or efficacy of ivermectin. Together, these findings indicate that ivermectin activates the GlyR by a novel mechanism.

Single-Channel Behavior of Heteromeric α1β Glycine Receptors: An Attempt to Detect a Conformational Change before the Channel Opens

“…Although the observed EC 50 value, 60 M, is well within the range reported for ␣1␤ heteromers in HEK293 cells (between 18 and 74 M) (Bormann et al, 1993;Handford et al, 1996;Rees et al, 2002), the Hill slope is at the top end of the range of values in the literature (1.8 -3.0) (Handford et al, 1996;Legendre, 1998;Shan et al, 2001). Most previous values were obtained by macroscopic methods and are inevitably more affected by desensitization than a P open concentration-response curve.…”

Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

“…In addition to nematode acetylcholine receptors, these targets also include P2X receptors of Schistosoma [32] and of mouse ( [33]) and histamine-gated chloride channels of Drosophila [34], as well as nematode [35][36][37][38] and insect [39,40] glutamate-gated chloride channels, GABA receptors from nematodes to vertebrates [41][42][43][44] and human glycine receptors [45]. There is also evidence for an action of IVM on an intracellular ligand-gated ion channel, the ryanodine receptor [46].…”

Incompatibility between a Pair of Residues from the Pre-M1 Linker and Cys-loop Blocks Surface Expression of the Glycine Receptor

“…Ivermectin is a GlyR agonist, which binds to the receptor and gates the channel via a different mechanism from that of glycine (23,24). It has been shown that ivermectin can induce currents in certain GlyRs with mutations that disrupt the glycine-activated channel gating pathway but leave surface expression intact (23). We wondered whether this was the case for the ␣chPm GlyR, as the pre-M1 linker is one of the essential components of the glycine-activated channel gating pathway (11)(12)(13)(14)(15).…”

“…Ivermectin is a GlyR agonist, which binds to the receptor and gates the channel via a different mechanism from that of glycine (23,24). It has been shown that ivermectin can induce currents in certain GlyRs with mutations that disrupt the glycine-activated channel gating pathway but leave surface expression intact (23).…”