Parasitic nematodes pose significant medical and veterinary problems, but chemotherapy to control many of these infections is limited. Most anthelminthics inhibit pharyngeal pumping/muscle contraction; therefore, the present study was designed to continue the characterization of the novel anaerobic mitochondria present in the parasitic nematode, Ascaris suum: The pyruvate dehydrogenase complex (PDC) plays a key role in regulating these anaerobic mitochondrial pathways and its regulation and subunit composition change dramatically during development. The PDC will be purified from aerobic larval stages and their regulation and subunit compositions compared to that of the adult PDC to characterize key modifications during these transitions. The regulations of the different subunit specific isoforms will be examined, using subunit resolution and the reconstitution of hybrid complexes. Finally, factors regulating the activity state of the PDC and end-product formation in isolated mitochondrial preparations will be examined directly. Ca++ does not appear to be an important signal linking muscle contraction with increased energy-generation in adult A. suum, as it does in vertebrate muscle. Instead, it appears that muscle contraction and energy-generation may both be potentially regulated by a variety of physiological ligands, including serotonin and FMRFamide-like neuropeptides, acting through a variety of second messenger systems. Therefore, muscle tension and pharyngeal pumping will be measured in vitro systems and will be correlated with ligand-dependent changes in second messenger levels, glucose/glycogen utilization, the activity states of key enzymes and end- product formation. These experiments should provide a wealth of critical base-line data on the hormonal regulation of pharyngeal pumping and muscle contraction, two key areas of anthelmintic development, and muscle metabolism, as well as key insights into how contraction and metabolism are linked.
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