Molecular characterization of the binding site of nematode GABA-A receptors
Date
2010-08-01
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Abstract
Haemonchus contortus is a parasitic nematode that is controlled in large part by
nematocidal drugs that target receptors of the parasitic nervous system. Hco-UNC-49 is a
nematode GABA receptor that has a relatively low overall sequence homology to
mammalian GABA receptors but is very similar to the UNC-49 receptor found in the free
living nematode Caenorhabditis elegans. However, the nematode receptors do exhibit
different sensitivities to GABA which may be linked to differences in the putative GABA
binding domains. Mutational analysis conducted in this study identified at least one
amino acid, positioned near the GABA binding domain, which may partially account for
differences in nematode GABA sensitivity. In addition, positions reported to be crucial
for GABA sensitivity in mammalian receptors also affect GABA sensitivity in Hco-
UNC-49 suggesting that the GABA binding domains of the mammalian and nematode
GABA receptors share some pharmacological similarities. However, there were some
differences observed. For example, in mammalian GABAA receptors amino acids from
both and subunits appear to be important for GABA sensitivity. For residues
examined in this study, only those on the UNC-49B subunit, and not UNC-49C, appear
important for GABA sensitivity.
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Keywords
Haemonchus contortus, GABA, Ligand binding, Mutational analysis, Homology modelling