The long term goal of this project is to understand the molecular basis of ion channel operation, specifically the mechanisms by which neurotransmitter binding is transduced into ion channel opening in the nicotinic acetylcholine receptor. Ion channels and receptors are important membrane proteins that govern information and energy flux between cellular compartments, and understanding their operation will help us understand cellular communication, excitability, and synaptic transmission. Moreover, a clear molecular picture of receptor mechanisms will help us understand the foundations of pharmacological action, i.e. the factors that influence drug potency. Ultimately, the knowledge gained will strengthen our ability to treat diseases that are caused by receptor or channel defects. The methods of single channel electrophysiology and molecular biology will be combined.
Three specific aims are 1) to explore new models of receptor activation via detailed kinetic analysis of cloned receptors expressed in oocytes, 2) to investigate structure/function relationships in these proteins by examining the effects of site-directed mutations and by studying chimeric channels, and 3) to construct large amounts of soluble subunit dimers that bind agonists and that could serve as a model system for later structural studies.
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