Gamma aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. The binding of GABA to postsynaptic GABA receptors opens a chloride-selective ion pore that is an integral component of the multimeric receptor complex. The resulting chloride flux across the cell membrane inhibits the postsynaptic neuron. Dysfunctions in GABA-mediated inhibition have been implicated in the etiology of a variety of neurological and psychological disorders. Furthermore, GABA receptors are a primary target for several neuroactive drugs including barbiturates, steroids, general anesthetics, and benzodiazepines (BZ); the latter of which is the subject of this proposal. Although it has been known for quite some time that BZs modulate GABA receptors, the molecular mechanism is still unresolved. This proposal will use a combination of molecular biology, electrophysiology, single oocyte radioactive ligand binding, and site directed fluorescent labeling to gain structural and functional insights into the actions of BZs on GABA receptors. Some of these techniques are new to the BZ field and it is hoped they will bring some fresh perspectives to the problem. ? The design of more efficacious BZs that can target the many different GABA receptor subtypes that have been identified in the brain will ultimately depend on understanding the structural requirements and precise mechanism of action of this important class of neuroactive compounds. The results from these proposed studies are expected to contribute to that effort. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036195-06
Application #
6722859
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (02))
Program Officer
Stewart, Randall R
Project Start
1997-04-01
Project End
2007-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
6
Fiscal Year
2004
Total Cost
$275,500
Indirect Cost
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Zheleznova, N; Sedelnikova, A; Weiss, D S (2008) alpha1beta2delta, a silent GABAA receptor: recruitment by tracazolate and neurosteroids. Br J Pharmacol 153:1062-71
Chang, Yongchang; Ghansah, Emmanuel; Chen, Yonghui et al. (2002) Desensitization mechanism of GABA receptors revealed by single oocyte binding and receptor function. J Neurosci 22:7982-90
Torres, Viviana I; Weiss, David S (2002) Identification of a tyrosine in the agonist binding site of the homomeric rho1 gamma-aminobutyric acid (GABA) receptor that, when mutated, produces spontaneous opening. J Biol Chem 277:43741-8
Ghansah, E; Weiss, D S (2001) Modulation of GABA(A) receptors by benzodiazepines and barbiturates is autonomous of PKC activation. Neuropharmacology 40:327-33
Filippova, N; Sedelnikova, A; Zong, Y et al. (2000) Regulation of recombinant gamma-aminobutyric acid (GABA)(A) and GABA(C) receptors by protein kinase C. Mol Pharmacol 57:847-56
Filippova, N; Dudley, R; Weiss, D S (1999) Evidence for phosphorylation-dependent internalization of recombinant human rho1 GABAC receptors. J Physiol 518 ( Pt 2):385-99
Wotring, V E; Chang, Y; Weiss, D S (1999) Permeability and single channel conductance of human homomeric rho1 GABAC receptors. J Physiol 521 Pt 2:327-36
Ghansah, E; Weiss, D S (1999) Benzodiazepines do not modulate desensitization of recombinant alpha1beta2gamma2 GABA(A) receptors. Neuroreport 10:817-21