REGULATION OF PHARYNGEAL PUMPING IN PARASITIC NEMATODES

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DESCRIPTION (provided by the applicant): Biogenic amines, such as serotonin, tyramine, octopamine and dopamine regulate a number of key processes in parasitic nematodes, including, feeding, pharyngeal pumping, locomotion, egg-laying and many more complex behaviors. During the previous grant period, we have begun to characterize the pharmacology, coupling and localization of a number of biogenic amine receptors in both free-living and parasitic nematodes with the goal of identifying the specific receptors regulating these key processes. During the course of these studies, we have also identified a novel tyraminergeric signaling pathway and presynaptic 5-HT receptor-linked signaling complexes that are localized by a multi-PDZ domain containing scaffolding protein that appear to be essential for efficient signal transduction. The present study is focused on the definitive identification of the biogenic amine receptors regulating pharyngeal pumping in the parasitic nematode, Ascaris suum, on the assumption that interference with these receptors, especially by stimulating inhibitory inputs, as has been described for ivermectin and glutamate-gated chloride channels, will have a deleterious effect of the worms. In addition, we hypothesize that receptor localization can be as important as receptor function for effective signal transduction and plan to test this hypothesis using mutants and a "dominant negative" approach, once the other components of these multi-protein signaling complexes have been confirmed by direct protein interaction and in vivo co-localization.