Montpied P, Ginns E I, Martin B M, Roca D, Farb D H, Paul S M
Section on Molecular Pharmacology, National Institute of Mental Health, Bethesda, Maryland 20892.
J Biol Chem. 1991 Apr 5;266(10):6011-4.
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.
γ-氨基丁酸（GABA）是大脑中的主要抑制性神经递质，已知它与一类能激活配体门控氯离子通道的受体相互作用。将培养的胚胎鸡神经元暴露于生理浓度的GABA会导致这些GABAA受体随时间下调。为了阐明负责激动剂诱导的GABAA受体下调的细胞机制，我们对GABAA受体α亚基信使核糖核酸的水平进行了定量，这些信使核糖核酸编码含有激动剂识别位点的亚基，并且在胚胎鸡神经元暴露于GABA后观察到α亚基信使核糖核酸显著减少。GABAA受体的下调以及GABA诱导的α亚基信使核糖核酸的减少都被特异性GABAA受体拮抗剂SR-95531完全拮抗。这些数据证明存在一种激动剂诱导的受体介导机制，用于调节编码受体亚基的信使核糖核酸的表达，这可能参与了对已知通过GABAA受体起作用的药物的药理作用产生耐受性的过程。
