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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043782-09
Application #
8305585
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (02))
Program Officer
Sutherland, Margaret L
Project Start
2002-04-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$338,851
Indirect Cost
$121,639
Name
University of Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Cai, En; Ge, Pinghua; Lee, Sang Hak et al. (2014) Stable small quantum dots for synaptic receptor tracking on live neurons. Angew Chem Int Ed Engl 53:12484-8
Baker, Lorinda K; Mao, Danyan; Chi, Henry et al. (2013) Intermittent nicotine exposure upregulates nAChRs in VTA dopamine neurons and sensitises locomotor responding to the drug. Eur J Neurosci 37:1004-11
Govind, Anitha P; Walsh, Heather; Green, William N (2012) Nicotine-induced upregulation of native neuronal nicotinic receptors is caused by multiple mechanisms. J Neurosci 32:2227-38
Singaraja, Roshni R; Huang, Kun; Sanders, Shaun S et al. (2011) Altered palmitoylation and neuropathological deficits in mice lacking HIP14. Hum Mol Genet 20:3899-909
Alexander, John K; Sagher, Daphna; Krivoshein, Arcadius V et al. (2010) Ric-3 promotes alpha7 nicotinic receptor assembly and trafficking through the ER subcompartment of dendrites. J Neurosci 30:10112-26
Govind, Anitha P; Vezina, Paul; Green, William N (2009) Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction. Biochem Pharmacol 78:756-65
Jeyifous, Okunola; Waites, Clarissa L; Specht, Christian G et al. (2009) SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nat Neurosci 12:1011-9
Drisdel, Renaldo C; Sharp, Douglas; Henderson, Tricia et al. (2008) High affinity binding of epibatidine to serotonin type 3 receptors. J Biol Chem 283:9659-65
Roth, Amy F; Wan, Junmei; Bailey, Aaron O et al. (2006) Global analysis of protein palmitoylation in yeast. Cell 125:1003-13
Yanai, Anat; Huang, Kun; Kang, Rujun et al. (2006) Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nat Neurosci 9:824-31