We have isolated clones encoding the members of the nicotinic acetylcholine receptor (nAChR) gene family, sequenced these clones, determined the loci in the rat brain of the cells that express the genes encoding these sequences, expressed these clones in the Xenopus oocyte to form functional neuronal nAChRs, and have discovered several interesting and unanticipated properties of the expressed receptors and of their synthesis. We also have used these clones, other new reagents we have created, and our knowledge of the properties of these receptors to address issues of their composition, assembly, disposition on the cell surface, and role in synapse formation. In the studies we are now proposing we will use the reductionist approach that has characterized our ongoing 30-year research endeavor, and for this phase of our studies focus intently on one specific nAChR subtype: the alpha7 nAChR. In our studies of the alpha7 nAChR we will focus on its physiologic roles, mechanisms of action, and its potential contribution to neurological disorders. In our studies we will ask the following questions: What are the hippocampal signal transduction mechanisms to which alpha7 nAChRs couple? What is the role of alpha7 nAChRs in the regulation of gene expression in the hippocampus? What is the role of the alpha7 nAChRs system in amyloid-beta peptide toxicity and Alzheimer's disease? These experiments are motivated by our new appreciation of the diversity of the ligand-gated ion channels and are designed to move our study of the neuronal nAChRs from the clones that encode them to the properties of the expressed proteins and their roles in synaptic function and modification in the central nervous system.
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