Steiger Janine L, Russek Shelley J
Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, Boston, MA 02118, USA.
Pharmacol Ther. 2004 Mar;101(3):259-81. doi: 10.1016/j.pharmthera.2003.12.002.
The type A gamma-aminobutyric acid (GABA(A)) receptors mediate the majority of fast inhibitory neurotransmission in the CNS, and alterations in GABA(A) receptor function is believed to be involved in the pathology of several neurological and psychiatric illnesses, such as epilepsy, anxiety, Alzheimer's disease, and schizophrenia. GABA(A) receptors can be assembled from eight distinct subunit families defined by sequence similarity: alpha(1-6), beta(1-3), gamma(1-3), delta, pi, theta, and rho(1-3). The regulation of GABA(A) receptor function in the brain is a highly compensating system, influencing both the number and the composition of receptors at the cell surface. While transcriptional and translational points of control operate in parallel, it is becoming increasingly evident that many functional changes in GABA(A) receptors reflect the differential gene regulation of its subunits. The fact that certain GABA(A) receptor subunit genes are transcribed in distinct cell types during specific periods of development strongly suggests that genetic control plays a major role in the choice of subunit variants available for receptor assembly. This review focuses on the physiological conditions that alter subunit mRNA levels, the promoters that may control such levels, and the use of a conceptual framework created by bioinformatics to study coordinate and independent GABA(A) receptor subunit gene regulation. As this exciting field moves closer to identifying the language hidden inside the chromatin of GABA(A) receptor subunit gene clusters, future experiments will be aimed at testing models generated by computational analysis with biologically relevant in vivo and in vitro assays. It is hoped that through this functional genomic approach there will be the identification of new targets for therapeutic intervention.
A型γ-氨基丁酸（GABA(A)）受体介导中枢神经系统中大部分快速抑制性神经传递，并且据信GABA(A)受体功能的改变与多种神经和精神疾病的病理过程有关，如癫痫、焦虑症、阿尔茨海默病和精神分裂症。GABA(A)受体可由八个不同的亚基家族组装而成，这些家族根据序列相似性定义：α(1-6)、β(1-3)、γ(1-3)、δ、π、θ和ρ(1-3)。大脑中GABA(A)受体功能的调节是一个高度补偿性系统，影响细胞表面受体的数量和组成。虽然转录和翻译控制点并行运作，但越来越明显的是，GABA(A)受体的许多功能变化反映了其亚基的差异基因调控。某些GABA(A)受体亚基基因在特定发育时期在不同细胞类型中进行转录，这一事实强烈表明遗传控制在可用于受体组装的亚基变体选择中起主要作用。本综述重点关注改变亚基mRNA水平的生理条件、可能控制此类水平的启动子，以及利用生物信息学创建的概念框架来研究GABA(A)受体亚基基因的协同和独立调控。随着这个令人兴奋的领域越来越接近识别隐藏在GABA(A)受体亚基基因簇染色质中的语言，未来的实验将旨在用生物学相关的体内和体外试验来测试计算分析生成的模型。希望通过这种功能基因组学方法能够识别出治疗干预的新靶点。
