Central nervous system (CNS) depression caused by ethanol is a complex phenomenon which may involve several neurotransmitter systems. The present study aims to probe in detail the molecular mechanisms by which ethanol perturbs glycine receptor function. A strong case can now be made for the involvement of glycine and gamma-aminobutyric acid (GABA) in the CNS depressant actions of ethanol; enhancement of the actions of these inhibitory transmitters is consistent with the sedative and anesthetic effects of ethanol. The glycine and GABA receptors are related members of the 'superfamily' of ligand-gated ion channels. Homomeric glycine alpha1 or alpha2 receptors, like native glycine receptors, are quite sensitive to modulation by ethanol; the actions of glycine are potentiated by ethanol. The homomeric GABA receptor formed by the beta1 subunit is strongly inhibited by ethanol. This proposal aims to study the molecular mechanism of glycine receptor modulation by ethanol, by using a series of chimeric receptors by exchange of large or small domains of the human glycine receptor alpha2 and human GABA receptor gamma1 subunits. The hypotheses to be tested are: 1) that the human glycine receptor cc subunit possesses specific structural features which permit enhancement of agonist action by ethanol, and 2) that specific amino acid residues can be identified in the glycine receptor .2 subunit that are permissive for ethanol modulation. It is important to investigate the mechanisms of action of ethanol in order to have knowledge of the molecular mechanisms of this most widely abused drug.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Small Research Grants (R03)
Project #
1R03AA011270-01
Application #
2000835
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1997-09-01
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Chicago
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637