An examination of interacting residues in the GABA-gated ion channel UNC-49 within the parasitic nematode Haemonchus contortus

Haemonchus contortus is a blood-feeding parasitic nematode that infects ruminant animals around the world, including those with significant economic importance such as cattle, sheep, and goats. UNC-49 is a GABA-gated chloride channel found to be exclusive to nematodes which could be a viable future target for anthelminthic drugs. An analysis of the model of the Hco-UNC-49 receptor has identified potentially interacting residues that may be important to its structure and function. One such potential interaction between\nK181 and E183, which appears to be unique to nematode GABA receptors, was selected for study based on charge and proximity to each other and the ligand binding site. A variety of mutations at these positions were introduced and analyzed by two-electrode voltage clamp electrophysiology. It was found that both residues are important for receptor function, but modifications to the E183 residue yielded a greater negative impact. It was also found that K181 and E183 are energetically coupled suggesting that they interact possibly through a salt-bridge. Disulfide trapping indicated that the two residues\nare in close enough proximity to directly interact. This analysis of key residues in a unique receptor could potentially be utilized for the future development of new anthelmintics to combat the increasing prevalence of infection by H. contortus.