STRUCTURE AND FUNCTION OF THE ACETYLCHOLINE RECEPTOR

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The objectives of the research application are to understand the structural features of the nicotinic acetylcholine receptor (AChR) and to relate these structures to the function of the receptor. The structure of the acetylcholine binding sites will be investigated by photoaffinity labelling to determine respective contributions of the subunits to the binding sites. Photoaffinity labels derivatized from d- tubocurarine, ethidium bromide and conotoxins will be designed to probe the contributions gamma- and delta-subunits to the agonist binding sites. The topology of the AChR primary subunit sequence will be analyzed by labelling of protein exposed on the extracellular surface of the AChR. The labelled sites will be identified by isolation of labelled fragments and identification of labelled residues. The location of putative intracellularly exposed fragment a156-179 will specifically be evaluated. Chemical crosslinking will be used to define near-neighbor relationships of the subunits and of individual amino acids within subunits.