The long-term goal of our research is to understand, on a molecular level, the control mechanisms that dynamically regulate neurotransmitter receptor distribution and function. The gamma-aminobutyric acid-A receptor (GABA-A-R) is of particular interest in this respect, both because it is one of the most widely distributed neurotransmitter receptors in the nervous system, and because it is a target for three important families of drugs-the benzodiazepines, the barbiturates, and the steroids-which bind to distinct modulatory sites on the GABA-A-R. Remarkably, the interaction of these modulators with the GABA-A-R is itself subject to regulation in response to chronic exposure to these and other drugs, including the transmitter, GABA. The goals of this proposal are to investigate mechanisms of GABA-A-R regulation in a primary monolayer cell culture system. Toward this end, the methods of radioligand binding, molecular biology, 36-Cl uptake, and electrophysiology will be employed to investigate the causes, mechanisms, and consequences of GABA-A-R regulation. In particular, we will define the pharmacology of GABA-A-R regulation by steroids, and will relate changes in GABA-A-R subunit gene expression to functional and ligand-binding properties of the receptor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023140-10
Application #
2264727
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1986-09-01
Project End
1996-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
10
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Boston University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Gyenes, M; Wang, Q; Gibbs, T T et al. (1994) Phosphorylation factors control neurotransmitter and neuromodulator actions at the gamma-aminobutyric acid type A receptor. Mol Pharmacol 46:542-9
Friedman, L; Gibbs, T T; Farb, D H (1993) Gamma-aminobutyric acidA receptor regulation: chronic treatment with pregnanolone uncouples allosteric interactions between steroid and benzodiazepine recognition sites. Mol Pharmacol 44:191-7
Celentano, J J; Gyenes, M; Gibbs, T T et al. (1991) Negative modulation of the gamma-aminobutyric acid response by extracellular zinc. Mol Pharmacol 40:766-73
Wu, F S; Gibbs, T T; Farb, D H (1991) Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor. Mol Pharmacol 40:333-6
Wu, F S; Gibbs, T T; Farb, D H (1990) Inverse modulation of gamma-aminobutyric acid- and glycine-induced currents by progesterone. Mol Pharmacol 37:597-602
Borden, L A; Gibbs, T T (1990) Flunitrazepam photoaffinity labeling of the GABA(A) receptor reduces inhibition of [3H]Ro15-4513 binding by GABA. Eur J Pharmacol 188:391-7
Roca, D J; Rozenberg, I; Farrant, M et al. (1990) Chronic agonist exposure induces down-regulation and allosteric uncoupling of the gamma-aminobutyric acid/benzodiazepine receptor complex. Mol Pharmacol 37:37-43
Roca, D J; Schiller, G D; Friedman, L et al. (1990) gamma-Aminobutyric acidA receptor regulation in culture: altered allosteric interactions following prolonged exposure to benzodiazepines, barbiturates, and methylxanthines. Mol Pharmacol 37:710-9
Czajkowski, C; Farb, D H (1989) Identification of an intracellular pool of gamma-aminobutyric acidA/benzodiazepine receptors en route to the cell surface of brain neurons in culture. Mol Pharmacol 35:183-8
Czajkowski, C; Gibbs, T T; Farb, D H (1989) Transmembrane topology of the gamma-aminobutyric acidA/benzodiazepine receptor: subcellular distribution and allosteric coupling determined in situ. Mol Pharmacol 35:75-84

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