Ivermectin, an unconventional agonist of the glycine receptor chloride channel.
The effects of the antihelmintic, ivermectin, were investigated in recombinantly expressed human alpha(1) homomeric and alpha(1)beta heteromeric glycine receptors (GlyRs). At low (0.03 microm) concentrations ivermectin potentiated the response to sub-saturating glycine concentrations, and at higher (> or =0.03 microm) concentrations it irreversibly activated both alpha(1) homomeric and alpha(1)beta 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.
Department of Physiology and Pharmacology, University of Queensland, Brisbane, Queensland 4072, Australia.
Q
Q
Shan
J L
JL
Haddrill
J W
JW
Lynch
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000502:physiology; D002460:Cell Line; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000502:physiology*; D019281:Dimerization; D005998:Glycine / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D007559:Ivermectin / Q000494:pharmacology*; D007668:Kidney; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D018009:Receptors, Glycine / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013331:Strychnine / Q000494:pharmacology
D065101:Chloride Channel Agonists; D018118:Chloride Channels; D007473:Ion Channels; D021122:Protein Subunits; D018009:Receptors, Glycine; D011994:Recombinant Proteins; D007559:Ivermectin; D013331:Strychnine; D005998:Glycine