Transport mechanisms and ion channels in nematodes

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Parasitic nematodes are a major cause of losses in livestock production, and are sources of ill health and death in animals and humans. In cattle, sheep, goats they are primarily controlled by treatment with anthelmintic drugs. Most of the existing anthelmintics act by disrupting transport mechanisms, involving ligand-gated ion channels. Anthelmintic resistance is becoming a problem for animal production throughout the world. Transport mechanisms involving ligand-gated ion channels and ABC transporters are involved in mechanisms of resistance. The transport systems in nematodes are different from those in mammals; some of these differences are responsible for the selective toxicity of anthelmintics against parasites. For example, the macrocyclic lactone anthelmintics, such as ivermectin, appear to target ligand-gated chloride channels (LGIC); some of which, e.g. glutamate-, dopamine-, serotonin-, and tyramine-gated Cl- channels do not occur in mammals. Other anthelmintics act on different classes of acetylcholine receptors, some of which are not found in mammals. Nematodes appear to have a rich and diverse array of ABC transport genes. Some membrane transporters appear to be involved in anthelmintic resistance. Differences between nematodes and mammals in these transport mechanisms may be propound. For example, humans have two P-glycoproteins, whereas nematodes may have up to 14 P-glycoproteins, 9 half transporters (similar to breast cancer resistant protein found in mammals), and 8 multidrug resistant protein genes, compared with 3 in mammals. The objectives of my research are to (a) characterize some of the transport genes and their products in nematodes which are divergent from those in mammals, to assess (b) their functions in nematodes, (c) to advance knowledge of the biology of parasitic nematodes and assess the possibilities of targeting divergent transport systems as novel targets for chemotherapy, (d) to determine their involvement with the action of anthelmintics, or (e) with mechanisms of resistance to anthelmintics. This information will be important for the development of novel means to control parasitic nematodes, with benefits to the animal industries, animal welfare and human health.