The identification of novel cys-loop receptor genes in Dirofilaria immitis
Nichols, Jennifer S.
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Dirofilaria immitis is a parasitic nematode responsible for canine heartworm disease. Currently, heartworm treatments rely primarily on a single drug class – the macrocyclic lactones – but anthelmintic resistance is emerging. Cys-loop ligand-gated ion channels are an untapped source for drug targets essential for nematode neurotransmission. This thesis presents the isolation and preliminary pharmacological characterization of three inhibitory D. immitis ion channels: GLC-2, GLC-4, and LGC-49. These genes are conserved across nematode species and expressed throughout the D. immitis life-cycle, as demonstrated by phylogenetic analysis and RT-qPCR. Dim-GLC-2 forms a monosodium L-glutamate (MSG) and L-glutamic acid sensitive homomeric channel, whereas the Dim-GLC-2/Dim-GLC-4 heteromeric channel shows reduced MSG current amplitude. The Dim-LGC-49 homomeric channel is responsive to cholinergic compounds. Homology modelling of homomeric channels highlights binding pocket residues which may interact with ligands. This research provides additional information on cys-loop receptors in parasitic nematodes crucial for understanding the action of potential new drugs.