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 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.
Lyons
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HR
Department of Pharmacology, Boston University School of Medicine, Massachusetts 02118, USA.
Gibbs
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Farb
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D000546:Amanitins / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D015536:Down-Regulation; D006207:Half-Life; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000546:Amanitins; D019384:Nucleic Acid Synthesis Inhibitors; D020033:Protein Isoforms; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid