Borden L A, Dhar T G, Smith K E, Branchek T A, Gluchowski C, Weinshank R L
Department of Pharmacology, Synaptic Pharmaceutical Corporation, Paramus, NJ 07652.
Recept Channels. 1994;2(3):207-13.
Molecular cloning has revealed the presence of four high-affinity GABA transporters in the brain. The existence of three of these sites, GAT-2, GAT-3, and BGT-1, was unknown prior to their cloning and almost nothing is known of the role they play in regulating GABAergic transmission. In large measure our paucity of knowledge is attributable to the lack of specific inhibitors for these sites. In the present communication we describe the cloning and expression of the human homologue of GAT-3, and the identification of an inhibitor, (S)-SNAP-5114, with selectivity for this site. (S)-SNAP-5114 displays an IC50 of 5 microM at GAT-3, 21 microM at GAT-2, and > or = 100 microM at GAT-1 and BGT-1. Due to its lipophilicity, (S)-SNAP-5114 is also expected to cross the blood-brain-barrier and therefore, should be an important tool for evaluating the role of GAT-3 in neural function.
分子克隆技术已揭示大脑中存在四种高亲和力γ-氨基丁酸（GABA）转运体。其中三个位点，即GAT - 2、GAT - 3和BGT - 1，在克隆之前并不为人所知，而且它们在调节GABA能传递中所起的作用几乎也无人知晓。很大程度上，我们知识的匮乏归因于缺乏针对这些位点的特异性抑制剂。在本通讯中，我们描述了GAT - 3人类同源物的克隆与表达，以及一种对该位点具有选择性的抑制剂（S）-SNAP - 5114的鉴定。（S）-SNAP - 5114在GAT - 3处的半数抑制浓度（IC50）为5微摩尔，在GAT - 2处为21微摩尔，在GAT - 1和BGT - 1处大于或等于100微摩尔。由于其亲脂性，预计（S）-SNAP - 5114也能穿过血脑屏障，因此，它应是评估GAT - 3在神经功能中作用的重要工具。
