gamma-Aminobutyric acid (GABA) induces a receptor-mediated reduction in GABAA receptor alpha subunit messenger RNAs in embryonic chick neurons in culture.
gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in brain, is known to interact with a subclass of receptors that activate a ligand-gated chloride ion channel. Exposure of cultured embryonic chick neurons to physiological concentrations of GABA results in a time-dependent down-regulation of these GABAA receptors. To delineate the cellular mechanism(s) responsible for agonist-induced down-regulation of GABAA receptors we quantified the levels of GABAA receptor alpha subunit messenger RNAs, which encode the subunit(s) containing agonist recognition site(s), and observed a marked reduction in alpha subunit mRNAs following exposure of embryonic chick neurons to GABA. Both the down-regulation of GABAA receptors and the reduction in alpha subunit mRNAs induced by GABA were completely antagonized by the specific GABAA receptor antagonist SR-95531. These data demonstrate the presence of an agonist-induced receptor-mediated mechanism for regulating the expression of receptor subunit-encoding mRNAs that may be involved in the development of tolerance to the pharmacological actions of drugs known to act via GABAA receptors.
Montpied
P
P
Section on Molecular Pharmacology, National Institute of Mental Health, Bethesda, Maryland 20892.
Ginns
E I
EI
Martin
B M
BM
Roca
D
D
Farb
D H
DH
Paul
S M
SM
D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D002642:Chick Embryo; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D018756:GABA Antagonists; D015640:Ion Channel Gating; D009474:Neurons / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011963:Receptors, GABA-A / Q000032:analysis / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018756:GABA Antagonists; D011724:Pyridazines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C049853:gabazine