Selective manipulation of the function of nicotinic acetylcholine receptors (nAChRs) may be beneficial in the treatment of a variety of disorders that impact mental and neurological health, including mood disorders, Parkinson's Disease, cognitive disorders and chronic pain. A major thrust of current research is to identify the subunits in the different functional channel subtypes of nAChRs and to understand their roles in health and disease. The availability of selective probes for the nAChR subtypes will greatly facilitate these efforts, and provide a platform for development of medications capable of modulating specific nAChR-mediated functions in the nervous system. Venoms from carnivorous marine snails of the genus Conus are an extraordinarily rich source of compounds (alpha-conotoxins) that potently and selectively target specific nAChR subtypes.
The aim of this proposal is to identify and characterize compounds from these venoms that discriminate among distinct acetylcholine-binding subunit interfaces of neuronal nAChRs.
This aim will be accomplished by using receptor-based assays to track the purification of active venom compounds. Genes encoding alpha-conotoxins will also be cloned to isolate new toxins. Peptides identified by either approach will be biochemically characterized and synthesized. These peptides will then be fully characterized with respect to receptor subtype specificity. Subsequently, synthetic strategies will be utilized to develop second-generation ligands with refined specificity. Structure/function studies will determine critical receptor binding residues. Using a combination of approaches, including the use of selective conotoxin probes, the molecular composition of native receptors will be functionally and biochemically defined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH053631-15
Application #
7807187
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Winsky, Lois M
Project Start
1996-09-30
Project End
2011-08-09
Budget Start
2010-05-15
Budget End
2011-08-09
Support Year
15
Fiscal Year
2010
Total Cost
$308,475
Indirect Cost
Name
University of Utah
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Liu, Liwang; Zhao-Shea, Rubing; McIntosh, J Michael et al. (2013) Nicotinic acetylcholine receptors containing the ?6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons. Biochem Pharmacol 86:1194-200
AlSharari, Shakir D; Carroll, F Ivy; McIntosh, J Michael et al. (2012) The antinociceptive effects of nicotinic partial agonists varenicline and sazetidine-A in murine acute and tonic pain models. J Pharmacol Exp Ther 342:742-9
Cohen, B N; Mackey, E D W; Grady, S R et al. (2012) Nicotinic cholinergic mechanisms causing elevated dopamine release and abnormal locomotor behavior. Neuroscience 200:31-41
Hone, Arik J; Meyer, Erin L; McIntyre, Melissa et al. (2012) Nicotinic acetylcholine receptors in dorsal root ganglion neurons include the ?6?4* subtype. FASEB J 26:917-26
McClure-Begley, Tristan D; Wageman, Charles R; Grady, Sharon R et al. (2012) A novel ?-conotoxin MII-sensitive nicotinic acetylcholine receptor modulates [(3) H]-GABA release in the superficial layers of the mouse superior colliculus. J Neurochem 122:48-57
Perez, Xiomara A; Ly, Jason; McIntosh, J Michael et al. (2012) Long-term nicotine exposure depresses dopamine release in nonhuman primate nucleus accumbens. J Pharmacol Exp Ther 342:335-44
Pérez-Alvarez, Alberto; Hernández-Vivanco, Alicia; McIntosh, J Michael et al. (2012) Native ?6?4* nicotinic receptors control exocytosis in human chromaffin cells of the adrenal gland. FASEB J 26:346-54
Brunzell, Darlene H; McIntosh, J Michael (2012) Alpha7 nicotinic acetylcholine receptors modulate motivation to self-administer nicotine: implications for smoking and schizophrenia. Neuropsychopharmacology 37:1134-43
Pérez-Alvarez, Alberto; Hernández-Vivanco, Alicia; Alonso Y Gregorio, Sergio et al. (2012) Pharmacological characterization of native ?7 nicotinic ACh receptors and their contribution to depolarization-elicited exocytosis in human chromaffin cells. Br J Pharmacol 165:908-21
Mackey, Elisha D W; Engle, Staci E; Kim, Mi Ran et al. (2012) ýý6* nicotinic acetylcholine receptor expression and function in a visual salience circuit. J Neurosci 32:10226-37

Showing the most recent 10 out of 88 publications