Activation of Cys-loop Receptors by Ivermectin

Timothy Lynagh (2011). Activation of Cys-loop Receptors by Ivermectin PhD Thesis, Queensland Brain Institute, The University of Queensland.

       
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Author Timothy Lynagh
Thesis Title Activation of Cys-loop Receptors by Ivermectin
School, Centre or Institute Queensland Brain Institute
Institution The University of Queensland
Publication date 2011-02
Thesis type PhD Thesis
Supervisor Professor Joseph W. Lynch
Total pages 115
Total colour pages 5
Total black and white pages 110
Subjects 11 Medical and Health Sciences
Abstract/Summary Ivermectin is a successful anthelmintic and insecticide that activates with nanomolar potency glutamate-gated chloride channels (GluClRs) that are present in invertebrate targets and absent in mammals. In recent years, it has been shown to enhance mammalian Cys-loop receptors, including the inhibitory glycine receptor (GlyR), but at micromolar concentrations. It is unclear how ivermectin interacts with these receptors, although evidence suggests that the binding site is distinct from that of normal agonists and likely in the transmembrane domain. The present study aimed to 1) identify structural differences between parasite GluClRs and the human GlyR that contribute to the large difference in potency at these receptors, 2) describe the ivermectin binding site and/or mechanism of activating the channel and 3) develop an ivermectin-sensitive receptor for neuronal silencing. The results suggested that the side-chain of one amino acid in the third membrane-spanning helix determines ivermectin sensitivity of GluClR and GlyR subunits and that this and other amino acids at an intersubunit interface are likely to interact with the ivermectin molecule. This information allowed for the development of a mutant GlyR that was sensitive to ivermectin and insensitive to glycine, that should serve as a neuronal silencing receptor.
Keyword Glycine Receptor
Ivermectin
cys-loop receptor
Anthelmintic
Insecticide
Nematode
Additional Notes Colour pages (pages refer to pdf document), 37, 39, 55, 58, 60.

 
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Created: Mon, 30 May 2011, 18:10:52 EST by Mr Timothy Lynagh on behalf of Library - Information Access Service