Synaptic transmission at chemical synapses in the CNS involves a relatively well-described sequences of events in which neurotransmitter is released from the presynaptic terminal and interacts with postsynaptic receptors that transduce ligand binding into a postsynaptic response. A major questions in neurobiology is how postsynaptic receptors are regulated to changing conditions. The GABAA/benzodiazepine receptor (GABA/BZD-R) is of particular interest in this respect, since the response to its transmitter, GABA, is allosterically modulated by benzodiazepines (BZDs) which act at a separate site on the GABA/BAD-R. Remarkably, the modulatory interaction of BZDs with th GABA/BZD-R is itself subject to regulation in response to chronic BZD exposure, and, moreover, the mode of regulation differs form that elicited by chronic exposure to GABAergic agonists. Whereas chronic exposure to GABAergic agonists results in down-regulation of GABA/BZD-R levels, chronic exposure to BZDs results in an """"""""uncoupling"""""""" of the allosteric interaction between the BZD recognition site and the GABA recognition site, with no change in receptor levels. Thus, the GABA/BZD-R exhibits two independent modes of homologous regulations: down-regulation induced by GABAergic agonists, and uncoupling induced by BZDs. Moveover, the GABA/BZD-R has now been found to exhibit heterologous regulation in response to chronic exposure to methylxanthines, such as caffeine and theophylline, which also produce uncoupling of GABA and BZD recognition sites, but which probably act through an adenosine receptor. The goal of this proposal is to investigate mechanism of homologous and heterologous GABA/BZD-R regulation in primary monolayer cell culture. Toward this end, the methods of radioligand binding, 36C1 uptake, and electrophysiology will be employed to determine the causes, mechanisms, and consequences of homologous and heterologous GABA/BZD-R regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS023140-05
Application #
3406340
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1986-09-01
Project End
1992-08-31
Budget Start
1990-09-07
Budget End
1991-08-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Boston University
Department
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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