Molecular characterization of the binding site of nematode GABA-A receptors

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.