Anthelmintic drug targets in the nematode neuromusculature

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Muscle coordination is a defining feature of all animals, targeted by toxins to induce paralysis and death. Coordination is maintained by neurotransmitter signalling, mediated by cell surface receptors that regulate the membrane voltage gradient. These pentameric ion-channel receptors are highly conserved in all animals and are fundamentally important to the study of animal biology. Parasitic helminths are second only to malaria for their impact on human health and productivity and are a major financial and management problem for agriculture. Drugs are the only effective means we have to control these parasites but the rise of resistance requires new drugs as well as techniques to extend the utility of drugs we have now. Most anthelmintics activate pentameric ion-channels, causing paralysis so the long term goal of my research is to understand how neurotransmitter control of parasitic nematode muscle is maintained, particularly in the face of developing anthelmintic resistance. The free living nematode, C. elegans, is perhaps the best characterized animal and as a close relative, has proved an extremely successful model for parasites. Targets of the major anthelmintic drugs have been identified and this knowledge transferred to parasitic nematodes. In every case, C. elegans ion-channel receptors are related but different from those in parasites. This difference poses the biggest immediate challenge for a deeper understanding of neurotransmitter control of parasite neuromusculature. The cause of anthelmintic resistance is not well understood but can involve loss of specific receptors, surprisingly, with little effect on normal muscle coordination. Redundant neurotransmitter receptors may be present with profound implications for drug combination therapies that are now recommended for parasite control. Resistance to one drug could prevent resistance to drugs that target a compensatory receptor. Plasticity of receptors observed between species may also be important if subunits are able to replace each other as resistance appears. My short term goals are to characterize new acetylcholine receptors in C. elegans and related parasites, determine if they represent redundant neurotransmitter control of muscle coordination, examine the mechanisms of receptor subunit assembly and specifically how these lead to differences between species. My novel approach is to identify and characterize gene duplications ideally suited to dissect the mechanism governing changing receptor composition. A major impact of this work will be understanding fundamental mechanisms of neurotransmitter circuitry and how receptors change between species. We will be able to identify new ion-channel receptors in different parasite species more effectively. It will establish the analysis of duplicate genes as a standard technique producing a paradigm-shift in the field of anthelmintic drug target research.