Borden L A
Trophix Pharmaceuticals Inc., South Plainfield, NJ 07080, USA.
Neurochem Int. 1996 Oct;29(4):335-56. doi: 10.1016/0197-0186(95)00158-1.
gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. GABA is cleared from the synaptic cleft by specific, high-affinity, sodium- and chloride-dependent transporters, which are thought to be located on presynaptic terminals and surrounding glial cells. While early studies suggested a distinction between neuronal and glial GABA transport, molecular cloning has revealed the existence of genes for four distinct GABA transporters (termed GAT-1, GAT-2, GAT-3 and BGT-1), thus revealing a greater heterogeneity than previously suspected. Heterologous expression has allowed a detailed characterization of their pharmacological properties, and has revealed that GAT-1 is the site of action of the anticonvulsant drug, Tiagabine. In-situ hybridization and immunocytochemistry demonstrate that each transporter has a unique regional distribution in the brain; in conjunction with experiments utilizing cell cultures, the neuronal vs glial localization of the various transporters is being elucidated. Future studies will be directed at determining the role of each transporter in the regulation of GABAergic transmission, and in the design of additional subtype-specific inhibitors, which may serve as novel therapeutic agents for the treatment of neuropsychiatric disorders.
γ-氨基丁酸（GABA）是哺乳动物大脑中的主要抑制性神经递质。GABA通过特异性、高亲和力、依赖钠和氯的转运体从突触间隙清除，这些转运体被认为位于突触前终末和周围的神经胶质细胞上。虽然早期研究表明神经元和神经胶质细胞对GABA的转运存在差异，但分子克隆揭示了四种不同GABA转运体（称为GAT-1、GAT-2、GAT-3和BGT-1）的基因存在，从而揭示了比以前怀疑的更大的异质性。异源表达使得能够详细表征它们的药理学特性，并揭示GAT-1是抗惊厥药物噻加宾的作用位点。原位杂交和免疫细胞化学表明，每种转运体在大脑中都有独特的区域分布；结合利用细胞培养的实验，正在阐明各种转运体在神经元与神经胶质细胞中的定位。未来的研究将致力于确定每种转运体在调节GABA能传递中的作用，以及设计额外的亚型特异性抑制剂，这些抑制剂可能作为治疗神经精神疾病的新型治疗药物。
