Acetylcholine (ACh) is one of the most important neurotransmitters in the peripheral and central nervous systems. However, it is increasingly recognized that ACh is also a key molecule for signaling via nicotinic acetylcholine receptors (nAChRs) in non-neuronal cells. Mounting evidence indicates that subtypes of ?9-containing nAChRs are critical receptors of ACh in these non-neuronal cells. These receptors are implicated in a plethora of functions including immune function, cell migration and the stress response. Consequently, these nAChRs have been implicated in diseases ranging from chronic pain to cancer-cell proliferation. Unfortunately, study of these ?9-containing nAChRs is severely limited because of the lack of selective ligands. There are no ligands selective for human ?9-containing nAChRs. Furthermore, existing ligands are unable to discriminate among ?9-containing nAChR subtypes in any tested species. To address this problem, conotoxins that are antagonists of ?9-containing nAChRs will be exploited.
Aim 1 will develop selective antagonists for the human ?9 nAChR. This will be accomplished through iterative synthesis of analogs of ?-conotoxin RgIA and by development of newly discovered ?-conotoxins.
Aim 2 will characterize, for the first time, new families of conotoxins that target ?9-containing nAChRs. These will be developed to enable the selective block of subtypes of these nAChRs. A long-term goal is to use existing ligands, together with newly developed toxins to gain mechanistic insight into the hypothesized role of ?9-containing nAChRs in preventing chronic pain that ensues following nerve injury.
Aim 3 will use developed ligands to study the role of block of ?9-containing nAChRs in models of breast cancer.

Public Health Relevance

This proposal will develop novel molecules for the study of cell surface proteins known as alpha9 nicotinic receptors. These receptors regulate diverse functions including immune system function and cell growth. The ability to pharmacologically manipulate these receptors has the therapeutic potential to treat chronic pain and breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM048677-21A1
Application #
8740926
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (40))
Project Start
Project End
Budget Start
2014-09-10
Budget End
2015-07-31
Support Year
21
Fiscal Year
2014
Total Cost
$279,481
Indirect Cost
$91,910
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Richter, K; Mathes, V; Fronius, M et al. (2016) Phosphocholine - an agonist of metabotropic but not of ionotropic functions of α9-containing nicotinic acetylcholine receptors. Sci Rep 6:28660
Safavi-Hemami, Helena; Li, Qing; Jackson, Ronneshia L et al. (2016) Rapid expansion of the protein disulfide isomerase gene family facilitates the folding of venom peptides. Proc Natl Acad Sci U S A 113:3227-32
Green, Brad R; Gajewiak, Joanna; Chhabra, Sandeep et al. (2016) Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin μO§-GVIIJ. J Biol Chem 291:7205-20
Hone, Arik J; McIntosh, J Michael; Rueda-Ruzafa, Lola et al. (2016) Therapeutic concentrations of varenicline in the presence of nicotine increase action potential firing in human adrenal chromaffin cells. J Neurochem :
Espino, Samuel S; Dilanyan, Taleen; Imperial, Julita S et al. (2016) Glycine-rich conotoxins from the Virgiconus clade. Toxicon 113:11-7
Zuo, Wanhong; Xiao, Cheng; Gao, Ming et al. (2016) Nicotine regulates activity of lateral habenula neurons via presynaptic and postsynaptic mechanisms. Sci Rep 6:32937
Curtice, Kigen J; Leavitt, Lee S; Chase, Kevin et al. (2016) Classifying neuronal subclasses of the cerebellum through constellation pharmacology. J Neurophysiol 115:1031-42
Yorgason, J T; Rose, J H; McIntosh, J M et al. (2015) Greater ethanol inhibition of presynaptic dopamine release in C57BL/6J than DBA/2J mice: Role of nicotinic acetylcholine receptors. Neuroscience 284:854-64
Lee, Hee-Kyoung; Zhang, Liuyin; Smith, Misty D et al. (2015) A marine analgesic peptide, Contulakin-G, and neurotensin are distinct agonists for neurotensin receptors: uncovering structural determinants of desensitization properties. Front Pharmacol 6:11
Aman, Joseph W; Imperial, Julita S; Ueberheide, Beatrix et al. (2015) Insights into the origins of fish hunting in venomous cone snails from studies of Conus tessulatus. Proc Natl Acad Sci U S A 112:5087-92

Showing the most recent 10 out of 238 publications