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J. Biol. Chem., Vol. 280, Issue 22, 20954-20960, June 3, 2005

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GABA Induces Activity Dependent Delayed-onset Uncoupling of GABA/Benzodiazepine Site Interactions in Neocortical Neurons^*

María C. Gravielle, Ramona Faris, Shelley J. Russek, and David H. Farb

From the Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118

Changes in the function of type A -aminobutyric acid receptors (GABA_ARs) are associated with neuronal development and tolerance to the sedative-hypnotic effects of GABA_AR positive modulators. Persistent activation of GABA_ARs by millimolar concentrations of GABA occurs under physiological conditions as GABAergic fast-spiking neurons in neocortex and cerebellum exhibit basal firing rates of 5 to 50 Hz and intermittent rates up to 250 Hz, leaving a substantial fraction of synaptic receptors occupied persistently by GABA. Persistent exposure of neurons to GABA has been shown to cause a down-regulation of receptor number and an uncoupling of GABA/benzodiazepine (BZD) site interactions with a half-life of 24 h. Here, we report that a single brief exposure of neocortical neurons in primary culture to GABA for 5–10 min (t = 3.2 ± 0.2 min) initiates a process that results in uncoupling hours later (t = 12.1 ± 2.2 h). Initiation of delayed-onset uncoupling is blocked by co-incubation with picrotoxin or -amanitin but is insensitive to nifedipine, indicating that uncoupling is contingent upon receptor activation and transcription but is not dependent on voltage-gated Ca²⁺ influx. Delayed-onset uncoupling occurs without a change in receptor number or a change in the proportion of 1 subunit pharmacology, as zolpidem binding affinity is unaltered. Such activity dependent latent modulation of GABA_AR function that manifests as delayed-onset uncoupling may be relevant to physiological, pathophysiological, and pharmacological conditions where synaptic receptors are transiently exposed to GABA agonists for several minutes.

Received for publication, January 5, 2005 , and in revised form, March 31, 2005.

^* This work was supported by the National Institute on Alcohol Abuse and Alcoholism and NICHD, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pharmacology, Boston, MA 02118. Tel.: 617-638-4480; Fax: 617-638-4329; E-mail: dfarb{at}bu.edu.

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