REGULATION OF PHARYNGEAL PUMPING IN PARASITIC NEMATODES

描述（由申请人提供）：生物胺，如血清素、酪胺、章鱼胺和多巴胺调节寄生线虫中的许多关键过程，包括进食、咽泵、运动、产卵和许多更复杂的行为。在上一个赠款期间，我们已经开始表征的药理学，耦合和本地化的一些生物胺受体在自由生活和寄生线虫的目标，确定特定的受体调节这些关键过程。 在这些研究的过程中，我们还确定了一种新的tyraminergeric信号通路和突触前5-HT受体连接的信号复合物，这些复合物由多PDZ结构域包含的支架蛋白定位，这些支架蛋白似乎对有效的信号转导至关重要。本研究的重点是明确识别的生物胺受体调节咽泵的寄生线虫，猪蛔虫，假设干扰这些受体，特别是通过刺激抑制输入，如已描述的伊维菌素和谷氨酸门控氯离子通道，将有有害的影响的蠕虫。此外，我们假设，受体定位可以作为重要的受体功能的有效信号转导，并计划测试这一假设使用突变体和“显性阴性”的方法，一旦这些多蛋白信号复合物的其他组件已被证实的直接蛋白质相互作用和体内共定位。

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.