Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056850-04
Application #
6138605
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
1998-01-01
Project End
2001-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
4
Fiscal Year
2000
Total Cost
$214,485
Indirect Cost

  Institution

Name
Weill Medical College of Cornell University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Melton, Elaina M; Cerny, Ronald L; DiRusso, Concetta C et al. (2013) Overexpression of human fatty acid transport protein 2/very long chain acyl-CoA synthetase 1 (FATP2/Acsvl1) reveals distinct patterns of trafficking of exogenous fatty acids. Biochem Biophys Res Commun 440:743-8
Melton, Elaina M; Cerny, Ronald L; Watkins, Paul A et al. (2011) Human fatty acid transport protein 2a/very long chain acyl-CoA synthetase 1 (FATP2a/Acsvl1) has a preference in mediating the channeling of exogenous n-3 fatty acids into phosphatidylinositol. J Biol Chem 286:30670-9
Sandoval, Angel; Chokshi, Aalap; Jesch, Elliot D et al. (2010) Identification and characterization of small compound inhibitors of human FATP2. Biochem Pharmacol 79:990-9
Arias-Barrau, Elsa; Dirusso, Concetta C; Black, Paul N (2009) Methods to monitor Fatty Acid transport proceeding through vectorial acylation. Methods Mol Biol 580:233-49
Sandoval, Angel; Fraisl, Peter; Arias-Barrau, Elsa et al. (2008) Fatty acid transport and activation and the expression patterns of genes involved in fatty acid trafficking. Arch Biochem Biophys 477:363-71
Li, Hong; Melton, Elaina M; Quackenbush, Steven et al. (2007) Mechanistic studies of the long chain acyl-CoA synthetase Faa1p from Saccharomyces cerevisiae. Biochim Biophys Acta 1771:1246-53
Tong, Fumin; Black, Paul N; Bivins, Lori et al. (2006) Direct interaction of Saccharomyces cerevisiae Faa1p with the Omi/HtrA protease orthologue Ynm3p alters lipid homeostasis. Mol Genet Genomics 275:330-43
Tong, Fumin; Black, Paul N; Coleman, Rosalind A et al. (2006) Fatty acid transport by vectorial acylation in mammals: roles played by different isoforms of rat long-chain acyl-CoA synthetases. Arch Biochem Biophys 447:46-52
DiRusso, Concetta C; Li, Hong; Darwis, Dina et al. (2005) Comparative biochemical studies of the murine fatty acid transport proteins (FATP) expressed in yeast. J Biol Chem 280:16829-37
Mashek, Douglas G; Bornfeldt, Karin E; Coleman, Rosalind A et al. (2004) Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family. J Lipid Res 45:1958-61

Showing the most recent 10 out of 18 publications