Rabow L E, Russek S J, Farb D H
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Massachusetts 02118, USA.
Synapse. 1995 Nov;21(3):189-274. doi: 10.1002/syn.890210302.
The gamma-aminobutyric acid type A (GABAA) receptor represents an elementary switching mechanism integral to the functioning of the central nervous system and a locus for the action of many mood- and emotion-altering agents such as benzodiazepines, barbiturates, steroids, and alcohol. Anxiety, sleep disorders, and convulsive disorders have been effectively treated with therapeutic agents that enhance the action of GABA at the GABAA receptor or increase the concentration of GABA in nervous tissue. The GABAA receptor is a multimeric membrane-spanning ligand-gated ion channel that admits chloride upon binding of the neurotransmitter GABA and is modulated by many endogenous and therapeutically important agents. Since GABA is the major inhibitory neurotransmitter in the CNS, modulation of its response has profound implications for brain functioning. The GABAA receptor is virtually the only site of action for the centrally acting benzodiazepines, the most widely prescribed of the anti-anxiety medications. Increasing evidence points to an important role for GABA in epilepsy and various neuropsychiatric disorders. Recent advances in molecular biology and complementary information derived from pharmacology, biochemistry, electrophysiology, anatomy and cell biology, and behavior have led to a phenomenal growth in our understanding of the structure, function, regulation, and evolution of the GABAA receptor. Benzodiazepines, barbiturates, steroids, polyvalent cations, and ethanol act as positive or negative modulators of receptor function. The description of a receptor gene superfamily comprising the subunits of the GABAA, nicotinic acetylcholine, and glycine receptors has led to a new way of thinking about gene expression and receptor assembly in the nervous system. Seventeen genetically distinct subunit subtypes (alpha 1-alpha 6, beta 1-beta 4, gamma 1-gamma 4, delta, p1-p2) and alternatively spliced variants contribute to the molecular architecture of the GABAA receptor. Mysteriously, certain preferred combinations of subunits, most notably the alpha 1 beta 2 gamma 2 arrangement, are widely codistributed, while the expression of other subunits, such as beta 1 or alpha 6, is severely restricted to specific neurons in the hippocampal formation or cerebellar cortex. Nervous tissue has the capacity to exert control over receptor number, allosteric uncoupling, subunit mRNA levels, and posttranslational modifications through cellular signal transduction mechanisms under active investigation. The genomic organization of the GABAA receptor genes suggests that the present abundance of subtypes arose during evolution through the duplication and translocations of a primordial alpha-beta-gamma gene cluster. This review describes these varied aspects of GABAA receptor research with special emphasis on contemporary cellular and molecular discoveries.
γ-氨基丁酸A型（GABAA）受体是中枢神经系统功能不可或缺的基本开关机制，也是许多改变情绪和情感的药物（如苯二氮䓬类、巴比妥类、类固醇和酒精）的作用位点。焦虑症、睡眠障碍和惊厥性疾病已通过增强GABA在GABAA受体上的作用或增加神经组织中GABA浓度的治疗药物得到有效治疗。GABAA受体是一种多聚体跨膜配体门控离子通道，在神经递质GABA结合后允许氯离子进入，并受到许多内源性和具有重要治疗意义的药物的调节。由于GABA是中枢神经系统中的主要抑制性神经递质，对其反应的调节对大脑功能具有深远影响。GABAA受体实际上是中枢作用苯二氮䓬类药物（最广泛使用的抗焦虑药物）的唯一作用位点。越来越多的证据表明GABA在癫痫和各种神经精神疾病中起重要作用。分子生物学的最新进展以及来自药理学、生物化学、电生理学、解剖学、细胞生物学和行为学的补充信息，使我们对GABAA受体的结构、功能、调节和进化的理解有了显著增长。苯二氮䓬类、巴比妥类、类固醇、多价阳离子和乙醇作为受体功能的正性或负性调节剂。一个包含GABAA、烟碱型乙酰胆碱和甘氨酸受体亚基的受体基因超家族的描述，引发了对神经系统中基因表达和受体组装的新思考方式。17种基因上不同的亚基亚型（α1-α6、β1-β4、γ1-γ4、δ、ρ1-ρ2）以及可变剪接变体构成了GABAA受体的分子结构。奇怪的是，某些亚基的优选组合，最显著的是α1β2γ2排列，广泛共分布，而其他亚基（如β1或α6）的表达则严格限于海马结构或小脑皮质中的特定神经元。神经组织有能力通过正在积极研究的细胞信号转导机制来控制受体数量、变构解偶联、亚基mRNA水平和翻译后修饰。GABAA受体基因的基因组组织表明，目前丰富的亚型是在进化过程中通过原始α-β-γ基因簇的复制和易位产生的。本综述描述了GABAA受体研究的这些不同方面，特别强调了当代细胞和分子发现。
