Central to synaptic transmission are the family of ionotropic neurotransmitter receptors, which are responsible for the rapid responses to neurotransmitters in nerve and muscle. In this proposal, a class of receptors that are members of this family, the neuronal nicotinic receptors, will be studied. As the site where nicotine binds in the brain, these receptors are responsible for nicotine addiction and may also play a role in neurodegenerative diseases such as Alzheimer's disease. Neuronal AChRs are composed of a number of subtypes as classified by their diverse pharmacology and distribution. One such subtype, the neuronal a-bungarotoxin binding receptor (BgtR) will be studied in this grant. We have found that that BgtRs are composed only of nicotinic a7 subunits and functional expression of a7 BgtRs only occurs in cells of neuronal origin. The first objective is to identify and characterize the neuronal-specific processing required for BgtR expression. The identification of posttranslational events that regulate BgtR expression in a neuronal-specific manner should provide insights into how other receptors and channels are regulated. The other objective is to determine the number of Bgt binding sites on BgtRs and to begin to characterize the BgtR Ab peptide binding sites. Ab peptides, which are play a critical role in the onset of Alzheimer's disease, bind to BgtRs, altering BgtR function and trigger second messenger changes within neurons. The hypotheses to be tested are that: 1) a7 subunit palmitoylation is one of a series of processing events required for expression of functional BgtRs; 2) there are four ligand binding sites on each BgtR and the sites can be distinguished by different affinities for antagonists; and 3) Ab peptides bind to a site on the BgtR extracellular surface different from the ligand binding sites.
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