Prolonged exposure to gamma-aminobutyric acid up-regulates stably expressed recombinant alpha 1 beta 2 gamma 2s GABAA 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 alpha1beta2gamma2s GABA(A) receptors for gamma-aminobutyric (GABA, 1 mM) and muscimol (100 microM), but not for diazepam (1 microM), enhanced the maximum number (B(max)) of [3H]flunitrazepam binding sites without affecting their affinity (K(d)). The GABA-induced enhancement in B(max) 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.
Pericić
Danka
D
Ruder Bosković Institute, Laboratory for Molecular Neuropharmacology, Division of Molecular Medicine, P.O. Box 180, 10002, Zagreb, Croatia. pericic@rudjer.irb.hr
Strac
Dubravka Svob
DS
Jembrek
Maja Jazvinsćak
MJ
Rajcan
Ivana
I
D002460:Cell Line; D018755:GABA Agonists / Q000378:metabolism / Q000494:pharmacology; D018756:GABA Antagonists / Q000378:metabolism / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006801:Humans; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000096:biosynthesis; D018079:Receptors, GABA / Q000096:biosynthesis; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage*
D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; C546240:GABRA1 protein, human; C546279:GABRG2 protein, human; C546241:Gabra1 protein, mouse; C470436:Gabrb2 protein, mouse; C546280:Gabrg2 protein, mouse; D021122:Protein Subunits; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid