engleski

Prolonged exposure to gamma-aminobutyric acid up-regulates stably expressed recombinant alpha1 beta2 gamma2s GABA A receptors

The aim of this study was to better understand the mechanisms that underlie adaptive changes in GABA A receptors following their prolonged exposure to drugs. Exposure (48 and/or 96 h) of human embryonic kidney (HEK 293) cells stably expressing recombinant alpha1 beta2 gamma2s GABA A receptors to gamma-aminobutyric (GABA, 1 mM) and muscimol (100 microM), but not to diazepam (1 microM), enhanced the maximum number (Bmax) of [3H]flunitrazepam binding sites without affecting their affinity (Kd). The GABA-induced enhancement in Bmax was reduced by the GABA receptor antagonist, bicuculline (100 microM), and by cycloheximide (10 microl/ml), a protein synthesis inhibitor. GABA (100 microM) enhanced the affinity of [3H]flunitrazepam binding to vehicle and GABA pretreated, but not to diazepam pretreated, HEK 293 cells. The results suggest that chronic GABA treatment up-regulates stably expressed GABA A receptors, presumably by stimulating their synthesis. Unlike chronic diazepam, which produced functional uncoupling of GABA and benzodiazepine binding sites, chronic GABA failed to produce this effect.

GABA A receptor; HEK 293 cells; gamma-aminobutyric acid; Diazepam; Muscimol; Radioligand binding

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