The objective of this project is to understand the molecular basis of the modulation of the GABAA receptor by three clinical intravenous anesthetic agents--propofol, etomidate, and methohexital. The strategy is to employ recombinant human receptors expressed in human embryonic kidney (HEK 293) or immortalized quail fibroblast (QT6) cells and to use whole cell patch clamp to record responses to transmitter application. There are four specific aims: 1: To test the hypothesis that the a subunit is important for modulation of receptor function by examining drug effects in heterooligomers in which the b and g subunits are constant and the a isoform is varied. 2. To examine the actions of these agents on related members of the ligand-gated chloride channel superfamily, including the glycine receptor and the r1 (GABAC) receptor, in order to determine the structural requirements for anesthetic action. 3. To construct chimeric receptors with GABAA a or b and r1 receptor portions to refine the specific structural features required for anesthetic action to portions of the respective subunits. 4. To pursue the structural requirements to the single amino acid level by constructing point mutations of the GABAA receptor using site-directed mutagenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056850-02
Application #
2857330
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1998-01-01
Project End
1999-10-31
Budget Start
1999-01-01
Budget End
1999-10-31
Support Year
2
Fiscal Year
1999
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
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