| dc.description.abstract | Haemonchus contortus is a parasitic nematode that infects the abomasum of
ruminants. While several classes of anthelmintic drugs exist to control nematode infections,
H. contortus is resistant to all of them. Therefore, novel drug targets such as ligand-gated
chloride channels (LGCCs) need to be characterized. The objective of this thesis was to
further characterize the agonist binding pocket in Hco-UNC-49BC, the LGCC gated by γ-
aminobutyric acid (GABA) within H. contortus. To meet this objective, each amino acid
residue in binding loop E was changed to a cysteine and analyzed via electrophysiology
and the substituted cysteine accessibility method. It was found that of the 18 loop E mutants
analyzed, His142, Ser144, Arg147, and Ser157, all played a role in channel activation and were
sensitive to modification by a methanethiosulfonate reagent. In addition, mutants lacking
His142 showed increased sensitivity to a variety of agonists and produced maximal chloride
conductance to the previously characterized partial agonist 5-aminovaleric acid. Overall,
this thesis has revealed potential differences in the agonist binding pocket between
nematode UNC-49 and mammalian GABA receptors that could be exploited in the design
of novel anthelmintics. | en |
