Neuronal nAChRs are composed of a number of subtypes as classified by their diverse pharmacology and distribution in the central and peripheral nervous system. We propose to study one such subtype, the neuronal a-bungarotoxin binding receptor (BgtR) in this grant application. BgtRs are unusual compared to other ionotropic neurotransmitter receptors in that they composed of single subunit subtype, the ?7 subunit. Additionally, ?7 subunits fail to fold and assemble into BgtRs in most cells and only form BgtRs in the correct cellular environment, mainly in neurons. Thus, ?7 subunits require one or more neuronal-specific processing events or neuronal-specific proteins in order to assemble into BgtRs. The overall goal of our research has been to identify and characterize the neuronal-specific processing events and proteins involved in BgtR expression. In the previous funding period, we were able to identify protein palmitoylation as a neuronal-specific posttranslational modification required for BgtR expression. We also have been characterizing a neuronal protein, Ric-3, that also helps mediate BgtR expression. The main objective of this proposal is to characterize the roles of subunit palmitoylation and Ric-3 in regulating BgtR expression when BgtRs are expressed heterologously or in neurons. Specifically, we will be identifying the machinery that palmitoylates ?7 subunits, testing for additional consequences of ?7 subunit palmitoylation, determining region of Ric-3 mediating its effects on BgtRs and examining how Ric-3 alters the posttranslational processing ?7 subunits. Ionotropic neurotransmitter receptors are essential for synaptic transmission and are responsible for the rapid responses to neurotransmitters in nerve and muscle. In this proposal, we will study the regulation of the expression of a specific neuronal nicotinic acetylcholine receptor (nAChR) subtype, the ?-bungarotoxin binding receptor (BgtR), which is an ionotropic neurotransmitter receptor. As the site where nicotine binds in the brain, these receptors are responsible for nicotine addiction and also play a role in neurodegenerative and psychiatric diseases such as Alzheimers disease and schizophrenia.

R01NS043782

2002-04-01

2013-07-31