The overall goals of the proposed research are to understand how transmitter-gated ion channels function, and the mechanisms by which cellular control processes and pharmacological agents modulate receptor function. To reach these goals, it is necessary to determine the steps and rates in receptor activation, to determine which rates are altered in cases in which function is altered, and to determine the likely structural bases for drug binding and actions. The proposed research focuses on the nicotinic acetylcholine receptor (AChR). Biophysical techniques will be used to study receptor function, biochemical techniques to study receptor structure, and molecular biological techniques to alter receptor structure. Continuing studies will utilize the muscle AChR to define the molecular features of the receptor which are involved in determining the channel opening rate. Additional projects will extend the research to neuronal AChRs, of which the functional properties and physiological roles are poorly understood. The research should provide basic information on the function of nicotinic receptors, and the mechanism by which pharmacological agents and cell processes affect function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022356-18
Application #
6477298
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Nichols, Paul L
Project Start
1984-12-01
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
18
Fiscal Year
2002
Total Cost
$246,664
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Jin, Xiaochun; Germann, Allison L; Shin, Daniel J et al. (2017) Determination of the Residues in the Extracellular Domain of the Nicotinic ? Subunit Required for the Actions of Physostigmine on Neuronal Nicotinic Receptors. Mol Pharmacol 92:318-326
Jin, Xiaochun; McCollum, Megan M; Germann, Allison L et al. (2017) The E Loop of the Transmitter Binding Site Is a Key Determinant of the Modulatory Effects of Physostigmine on Neuronal Nicotinic ?4?2 Receptors. Mol Pharmacol 91:100-109
Bracamontes, John R; Akk, Gustav; Steinbach, Joe Henry (2016) Introduced Amino Terminal Epitopes Can Reduce Surface Expression of Neuronal Nicotinic Receptors. PLoS One 11:e0151071
Jin, Xiaochun; Steinbach, Joe Henry (2015) Potentiation of Neuronal Nicotinic Receptors by 17?-Estradiol: Roles of the Carboxy-Terminal and the Amino-Terminal Extracellular Domains. PLoS One 10:e0144631
Haller, Gabe; Li, Ping; Esch, Caroline et al. (2014) Functional characterization improves associations between rare non-synonymous variants in CHRNB4 and smoking behavior. PLoS One 9:e96753
Jin, Xiaochun; Bermudez, Isabel; Steinbach, Joe Henry (2014) The nicotinic ?5 subunit can replace either an acetylcholine-binding or nonbinding subunit in the ?4?2* neuronal nicotinic receptor. Mol Pharmacol 85:11-7
Akk, Gustav; Eaton, Megan; Li, Ping et al. (2013) Energetic contributions to channel gating of residues in the muscle nicotinic receptor ?1 subunit. PLoS One 8:e78539
Haller, Gabe; Druley, Todd; Vallania, Francesco L et al. (2012) Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence. Hum Mol Genet 21:647-55
Tammimäki, Anne; Herder, Penelope; Li, Ping et al. (2012) Impact of human D398N single nucleotide polymorphism on intracellular calcium response mediated by ?3?4?5 nicotinic acetylcholine receptors. Neuropharmacology 63:1002-11
Hinrichs, Anthony L; Murphy, Sharon E; Wang, Jen C et al. (2011) Common polymorphisms in FMO1 are associated with nicotine dependence. Pharmacogenet Genomics 21:397-402

Showing the most recent 10 out of 54 publications