Neurobiological processes play a vital role in the survival and reproductive fitness of Schistosoma mansoni, a blood fluke which is the causative agent of schistosomiasis, a medically important human disease in much of the world. Our short term goal is to characterize those neurotransmitter receptors of the parasite that play a direct role in regulating muscle cell activity and in the longrun utilize this information to design antischistosomal drugs. We have developed methods for isolating single muscle fibers from adult schistosomes and have been able, for the first time, to directly analyze the pharmacological nature of receptors on these fibers and then manipulate these fibers, using patch clamp technology, to answer the question of how these receptors regulate ion channel activity on their surface. Furthermore, we are utilizing standard molecular techniques to clone, sequence and express these ion channels. This application is an extension of our previous work and will employ the methods described above. We will focus on two rather unique schistosome receptors, a amidated peptide receptor and a receptor for the amino-acid glutamate. Both of these agents produce dramatic effects upon schistosome muscle fibers but as neurotransmitters in the mammalian host they only function within the central nervous system thus making them attractive targets for drug developers. Our objective is to completely characterize the pharmacological nature of these receptors, determine how they regulate ion conductance across the muscle fiber membrane and the nature of the second messengers which mediate these receptor-induced changes in the permeability of muscle fibers to ions. Once we have completely characterized a receptor, we will clone and sequence it to evaluate its molecular nature and then express the receptor in a surrogate cell to confirm if its pharmacological and physiological properties are identical to those obtained from studies of the receptor in schistosome muscle fibers. Collectively our research on receptors which regulate the excitability of schistosome muscle cells will provide detailed information on macromolecules which play a vital role in regulating parasite behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030465-07
Application #
2672029
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1991-08-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
2000-07-31
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Michigan State University
Department
Zoology
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Cobbett, Peter; Day, Timothy A (2003) Functional voltage-gated Ca2+ channels in muscle fibers of the platyhelminth Dugesia tigrina. Comp Biochem Physiol A Mol Integr Physiol 134:593-605
Day, T A; Haithcock, J; Kimber, M et al. (2000) Functional ryanodine receptor channels in flatworm muscle fibres. Parasitology 120 ( Pt 4):417-22
Miller, C L; Day, T A; Bennett, J L et al. (1996) Schistosoma mansoni: L-glutamate-induced contractions in isolated muscle fibers;evidence for a glutamate transporter. Exp Parasitol 84:410-9
Day, T A; Chen, G Z; Miller, C et al. (1996) Cholinergic inhibition of muscle fibres isolated from Schistosoma mansoni (Trematoda:Digenea). Parasitology 113 ( Pt 1):55-61
Day, T A; Bennett, J L; Pax, R A (1994) Serotonin and its requirement for maintenance of contractility in muscle fibres isolated from Schistosoma mansoni. Parasitology 108 ( Pt 4):425-32
Day, T A; Orr, N; Bennett, J L et al. (1993) Voltage-gated currents in muscle cells of Schistosoma mansoni. Parasitology 106 ( Pt 5):471-7