A NOVEL CLASS OF MAMMALIAN GABA RECEPTOR

神经元抑制是大脑功能的基础，在脊椎动物中， 主要的抑制性神经递质是γ-氨基丁酸(GABA)。 GABA能系统的功能障碍似乎与该疾病的发生有关 许多神经和精神疾病，如癫痫， 肌阵挛、抑郁和焦虑，并可能在 亨廷顿病、精神分裂症和酗酒。在哺乳动物中，有 两个特性良好的GABA受体家族。GABA-A受体是 配体门控的氯离子通道，该通道可被 惊厥生物碱荷包牡丹碱。GABA-B受体偶联GTP结合 蛋白质和细胞内信使途径，并具有立体特异性 由(-)巴氯芬激活。GABA-A受体似乎是 调节治疗有用药物的作用，如苯二氮卓类药物 和巴比妥酸盐，以及酒精的一些镇静作用。 选择性地与GABA-B受体相互作用的药物目前正在开发中 可用于治疗痉挛、癫痫和 抑郁症。 利用青蛙卵母细胞的RNA表达研究，我们发现了一种新的 哺乳动物的一类GABA受体，具有药理和电学功能 明显区别于GABA-A或GABA-B的特性。这 受体对GABA有很高的亲和力，但对荷包牡丹碱不敏感 和巴氯芬，不受苯二氮卓类或巴比妥酸盐调节。在……里面 鉴于其他类别的GABA受体在中枢神经系统中的重要性，我们 建议对其结构、药理和电学特性进行表征 这些新型GABA受体的特性。这将是一个初步的步骤 开发与该站点特定相互作用的药物，并将 为了解其所起的生理作用奠定了基础 荷包牡丹碱/巴氯芬不敏感的GABA受体在精神功能和 健康。

Neuronal inhibition is fundamental to brain function, and in vertebrates, the major inhibitory neurotransmitter is gamma-aminobutyric (GABA). Dysfunction of GABA-ergic systems appears to be involved in the development of numerous neurological and psychiatric diseases such as epilepsy, myoclonus, depression and anxiety, and might also play roles in Huntington's disease, schizophrenia and alcoholism. In mammals there are two well characterized families of GABA receptors. GABA-A receptors are ligand-gated Cl- channels, which are specifically antagonized by the convulsive alkaloid bicuculline. GABA-B receptors couple to GTP-binding proteins and intracellular messenger pathways, and are stereospecifically activated by (-)baclofen. GABA-A receptors appear to be the site which mediates actions of therapeutically useful drugs such as benzodiazepines and barbiturates, together with some of the sedative effects of alcohol. Drugs which selectively interact with GABA-B receptors are presently being developed, and could be of value in treating spasticity, seizure, and depression. Using RNA expression studies in frog oocytes, we have detected a novel class of mammalian GABA receptor, with pharmacological and electrical properties which clearly distinguish it from GABA-A or GABA-B. This receptor has high affinity for GABA, but is insensitive to both bicuculline and baclofen, and is not modulated by benzodiazepines or barbiturates. In view of the importance of other classes of GABA receptor in the CNS, we propose to characterize the structure, pharmacology and electrical properties of these novel GABA receptors. This will be a preliminary step in developing drugs which interact specifically with this site, and will provide a foundation for understanding the physiological roles played by bicuculline/baclofen-insensitive GABA receptors in mental function and health.