Turnover and down-regulation of GABA(A) receptor alpha1, beta2S, and gamma1 subunit mRNAs by neurons in culture

Benzodiazepines (BZDs), barbiturates, ethanol, and general anesthetics potentiate the action of gamma-aminobutyric acid (GABA) at the type A GABA receptor (GABA(A)R) and have profound effects on mood, arousal, and susceptibility to seizures. GABA(A)R number and subunit mRNA levels change in animal m...

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Bibliographic Details
Published in:Journal of neurochemistry 2000-03, Vol.74 (3), p.1041
Main Authors: Lyons, H R, Gibbs, T T, Farb, D H
Format: Article
Language:English
Subjects:
Amanitins - pharmacology
Animals
Cells, Cultured
Chick Embryo
Down-Regulation
gamma-Aminobutyric Acid - pharmacology
Half-Life
Neurons - drug effects
Neurons - metabolism
Nucleic Acid Synthesis Inhibitors - pharmacology
Protein Isoforms - genetics
Receptors, GABA-A - genetics
RNA Stability - drug effects
RNA, Messenger - metabolism
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Summary:Benzodiazepines (BZDs), barbiturates, ethanol, and general anesthetics potentiate the action of gamma-aminobutyric acid (GABA) at the type A GABA receptor (GABA(A)R) and have profound effects on mood, arousal, and susceptibility to seizures. GABA(A)R number and subunit mRNA levels change in animal models of epilepsy and anxiety and following exposure to GABA(A)R agonists and positive modulators, but the mechanism of receptor down-regulation remains unknown. Persistent exposure (48 h) of brain neurons in primary culture to GABA results in a 30% decrease in the levels of mRNA encoding the alpha1, beta2S, and gamma1 GABA(A)R subunit isoforms, which form a receptor enhanced by nonselective BZDs. Down-regulation of alpha1 mRNA (t1/2 = 8 h) precedes down-regulation of receptor number (t1/2 = 25 h), suggesting that GABA-induced GABA(A)R down-regulation is a consequence of decreased mRNA levels. The apparent half-life of the alpha1 mRNA in the presence of alpha-amanitin (9 h) is consistent with the time course of alpha1 mRNA down-regulation. Moreover, the stability of the alpha1, beta2S, and gamma1 subunit mRNAs is not altered by chronic GABA exposure. The results demonstrate that GABA(A)R subunit mRNA down-regulation is not a consequence of accelerated mRNA degradation and argue that GABA-induced GABA(A)R down-regulation is due to inhibition of transcription.
ISSN:0022-3042
1471-4159