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 17 subunit. Additionally, 17 subunits fail to fold and assemble into BgtRs in most cells and only form BgtRs in the correct cellular environment, mainly in neurons. Thus, 17 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 17 subunits, testing for additional consequences of 17 subunit palmitoylation, determining region of Ric-3 mediating its effects on BgtRs and examining how Ric-3 alters the posttranslational processing 17 subunits.

Public Health Relevance

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 1-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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-C (02))
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Sutherland, Margaret L
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University of Chicago
Schools of Medicine
United States
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Jeyifous, Okunola; Lin, Eric I; Chen, Xiaobing et al. (2016) Palmitoylation regulates glutamate receptor distributions in postsynaptic densities through control of PSD95 conformation and orientation. Proc Natl Acad Sci U S A 113:E8482-E8491
Zheng, Ning; Jeyifous, Okunola; Munro, Charlotte et al. (2015) Synaptic activity regulates AMPA receptor trafficking through different recycling pathways. Elife 4:
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
Lin, Eric I; Jeyifous, Okunola; Green, William N (2013) CASK regulates SAP97 conformation and its interactions with AMPA and NMDA receptors. J Neurosci 33:12067-76
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
Antinone, Sarah E; Ghadge, Ghanashyam D; Lam, Tukiet T et al. (2013) Palmitoylation of superoxide dismutase 1 (SOD1) is increased for familial amyotrophic lateral sclerosis-linked SOD1 mutants. J Biol Chem 288:21606-17
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
Alexander, J K; Govind, A P; Drisdel, R C et al. (2010) Palmitoylation of nicotinic acetylcholine receptors. J Mol Neurosci 40:12-20

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