The purpose of the proposed research is to study the function and structure of the nicotinic acetylcholine receptor (AChR) and then to describe the results cohesively in terms of the amino acid sequences of the receptor subunits. A better understanding of single AChRs will then serve as a background for exploring the AChR's involvement in complex processes at the neuromuscular junction. Electrophysiological techniques, theoretical approaches, fluorescent ion indicators, and biophysical studies of structure will provide a body of information to guide site-directed mutagenesis experiments with the AChR. The mutation studies allow direct comparison of structure and function to test existing hypotheses and to generate better ones. Calcium's permeability, interactions with other permeants, and influence on protein phosphorylation will be examined as a possible unique self-regulating mechanism of AChRs at the neuromusclar junction. Quantifying and determining the biological importance of calcium entry through AChRs is not only important at cholinergic synapses; it also could suggest regulatory roles of calcium that enters the cell through other synaptic receptors not known primarily as Ca channels. The proposed research directly relates the structure and function of the AChR to its overall roles at the neuromuscular endplate. In addition, the studies will contribute to the general understanding of possible mechanisms involved in regulating synapses.
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