The goal of this research is to characterize the molecular mechanism of acetylcholine receptor function including: 1) the binding of specific ligands, 2) the coupling between ligand binding and ion permeability, 3) the ion permeation mechanism and 4) desensitization, a process in which ion permeability is blocked in the prolonged presence of activating ligands. The emphasis in this project is on membrane interactions that are important in the regulation of the above processes. Spectroscopic techniques, such as electron paramagnetic resonance and fluorescence, will be used to provide detailed information about lipid and protein dynamics and lipid-protein interactions. Most experiments will be carried out on both native and reconstituted membrane vesicles prepared from the electric tissue of the electric ray Torpedo californica. Ion fluxes will be measured on the millesecond time scale using rapid kinetics techniques. The acetylcholine receptor is an essential component in synaptic transmission and the experiments will provide detailed information about normal nerve and muscle interactions. In addition, the acetylcholine receptor is one of the few integral membrane proteins that can be studied in biochemical detail at many different levels of cellular organization. Thus the membrane phenomena important for this receptor may also be important for other receptor systems in the central nervous system that are more difficult to analyze.
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