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J. Biol. Chem., Vol. 276, Issue 16, 12556-12564, April 20, 2001
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From the Department of Physiology and Pharmacology, University of
Queensland, Brisbane, Queensland 4072, Australia
The effects of the antihelmintic,
ivermectin, were investigated in recombinantly expressed human
Ivermectin, an Unconventional Agonist of the Glycine Receptor
Chloride Channel*
,
1 homomeric and 1
heteromeric glycine receptors (GlyRs). At low (0.03 µM)
concentrations ivermectin potentiated the response to sub-saturating
glycine concentrations, and at higher (
0.03 µM)
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.
*
This work was supported in part by the Australian Research
Council.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by an Ernest Singer Postgraduate Scholarship from the
University of Queensland.
§
To whom correspondence should be addressed: Dept. of Physiology and
Pharmacology, University of Queensland, Brisbane, Queensland 4072, Australia. Tel.: 617-3365-3157; Fax: 617-3365-1766; E-mail: lynch@plpk.uq.edu.au.
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