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.
