The Dirofilaria immitis unc-49 gene encodes a pharmacologically unique cys-loop GABA receptor

Abstract

Nematode cys-loop GABA receptors play important roles in movement and locomotion. GABA receptors encoded by unc-49 appear to be widespread in nematode genomes including parasitic nematodes but are poorly characterized in filarial parasites. Dirofilaria immitis is a filarial parasite responsible for heartworm disease in dogs. Macrocyclic lactones are widely used to prevent heartworm infection. However, like many anthelmintics, resistance has emerged and new solutions are needed including the discovery of new anthelmintic drug targets. In this study, we report the isolation of two unc-49 subunit mRNAs (unc-49b and unc-49c) from the canine parasitic nematode D. immitis. When expressed in Xenopus oocytes, Dim-UNC-49B formed a functional homomeric GABA-gated channel, whereas Dim-UNC-49C did not. We further demonstrated that Dim-UNC-49B and Dim-UNC-49C gave rise to a functional heteromeric channel. Pharmacological characterization of these receptors and cross-species co-expression with UNC-49 subunits from the parasitic nematode Haemonchus contortus showed some unique properties compared to the same receptors characterized from other nematodes. These results revealed new properties of UNC-49 receptors in filarial worms.