Abstract

The behavioral and cognitive changes induced by ethanol have recently been traced to alterations in the activity of several neurotransmitter- gated ion channels. It has been hypothesized that alcohols bind specifically to these proteins, altering their conformation and ability to transport ions across membranes. This hypothesis may now be addressed by determining the effect of alcohols on the conformation and ligand binding properties of neurotransmitter receptors. In this project we use multidimensional heteronuclear magnetic resonance spectroscopy to focus on the atomic-resolution structure of the strychnine-sensitive glycine receptor whose involvement in the central depressant effects of ethanol has recently been established. We will focus on a extracellular domain of the glycine receptor due to its size, apparent solubility and ability to bind glycine, strychnine, and ethanol. The structural and biochemical results of this project will provide a detailed mechanism of alcohol action and aid in the design of novel compounds that combat the depressant and addictive effects of alcohol.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
2P50AA003527-21
Application #
6267052
Study Section
Project Start
1997-12-01
Project End
1998-11-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Bennett, B; Carosone-Link, P; Beeson, M et al. (2008) Genetic dissection of quantitative trait locus for ethanol sensitivity in long- and short-sleep mice. Genes Brain Behav 7:659-68
Vasiliou, Vasilis; Ziegler, Thomas L; Bludeau, Pequita et al. (2006) CYP2E1 and catalase influence ethanol sensitivity in the central nervous system. Pharmacogenet Genomics 16:51-8
Bowers, Barbara J; Miyamoto-Ditmon, Jill; Wehner, Jeanne M (2006) Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cgamma. Pharmacol Biochem Behav 85:441-7
Zimatkin, Sergey M; Pronko, Sergey P; Vasiliou, Vasilis et al. (2006) Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res 30:1500-5
Radcliffe, Richard A; Bludeau, Pequita; Asperi, William et al. (2006) Confirmation of quantitative trait loci for ethanol sensitivity and neurotensin receptor density in crosses derived from the inbred high and low alcohol sensitive selectively bred rat lines. Psychopharmacology (Berl) 188:343-54
Smith, Amy M; Bowers, Barbara J; Radcliffe, Richard A et al. (2006) Microarray analysis of the effects of a gamma-protein kinase C null mutation on gene expression in striatum: a role for transthyretin in mutant phenotypes. Behav Genet 36:869-81
Bowers, Barbara J; Radcliffe, Richard A; Smith, Amy M et al. (2006) Microarray analysis identifies cerebellar genes sensitive to chronic ethanol treatment in PKCgamma mice. Alcohol 40:19-33
Haughey, Heather M; Kaiser, Alan L; Johnson, Thomas E et al. (2005) Norepinephrine transporter: a candidate gene for initial ethanol sensitivity in inbred long-sleep and short-sleep mice. Alcohol Clin Exp Res 29:1759-68
Wu, Peter H; Poelchen, Wolfgang; Proctor, William R (2005) Differential GABAB Receptor Modulation of Ethanol Effects on GABA(A) synaptic activity in hippocampal CA1 neurons. J Pharmacol Exp Ther 312:1082-9
Quertemont, Etienne; Eriksson, C J Peter; Zimatkin, Sergey M et al. (2005) Is ethanol a pro-drug? Acetaldehyde contribution to brain ethanol effects. Alcohol Clin Exp Res 29:1514-21

Showing the most recent 10 out of 355 publications