GABA-INDUCED UNCOUPLING OF GABA/BENZODIAZEPINE SITE INTERACTIONS IS MEDIATED BY INCREASED GABA_A RECEPTOR INTERNALIZATION AND ASSOCIATED WITH A CHANGE IN SUBUNIT COMPOSITION

摘要

Persistent activation of GABA_A receptors triggers compensatory changes in receptor function that are relevant to physiological, pathological and pharmacological conditions. Chronic treatment of cultured neurons with GABA for 48 h has been shown to produce a down-regulation of receptor number and an uncoupling of GABA/benzodiaze-pine site interactions with a half-time of 24-25 h. Down-regulation is the result of a transcriptional repression of GABA_A receptor subunit genes and depends on activation of L-type voltage-gated calcium channels. The mechanism of this uncoupling is currently unknown. We have previously demonstrated that a single brief exposure of rat primary neocortical cultures to GABA for 5-10 min (t 1/2 = 3 min) initiates a process that results in uncoupling hours later (t 1/2 = 12 h) without a change in receptor number. Uncoupling is contingent upon GABA_A receptor activation and independent of voltage-gated calcium influx. This process is accompanied by a selective decrease in subunit mRNA levels. Here, we report that the brief GABA exposure induces a decrease in the percentage of