Structure and function of the dopamine transporter
Structure and function of the dopamine transporter
复制标题
DOI：
10.1016/s0014-2999(00)00563-x
复制
发表时间：
2000-09-29
影响因子：
5
通讯作者：
Reith, MEA
中科院分区：
文献类型：
--
作者：
Chen, NH;Reith, MEA
多巴胺转运体介导多巴胺进入神经元的摄取，是各种药理活性药物和环境毒素的主要靶点。自其克隆以来，有关其结构和功能的信息已有很多。多巴胺和包括可卡因在内的各种阻断药物的结合域可能是通过与多个氨基酸残基相互作用形成的，其中一些氨基酸残基在一级结构中是分开的，但在仍未知的三级结构中紧密相连。嵌合体和定点突变研究表明，重叠和分离的结构域都参与了与底物和阻断剂的相互作用，而最近的发现，重叠和分离的结构域参与了与底物和NAD阻断剂的相互作用，与可卡因等阻滞剂的结合。多巴胺转运体也可以反向操作，即以外排模式工作，最近的突变实验表明，内向和外向转运的结构要求不同。多巴胺转运体结构域选择性地影响多巴胺或可卡因类似物的结合的有力证据尚未出现，尽管在转运体水平上开发可卡因拮抗剂仍然是可能的。(C)2000 Elsevier Science B.V.保留所有权利。
The dopamine transporter mediates uptake of dopamine into neurons and is a major target for various pharmacologically active drugs and environmental toxins. Since its cloning, much information has been obtained regarding its structure and function. Binding domains for dopamine and various blocking drugs including cocaine an likely formed by interactions with multiple amino acid residues, some of which are separate in the primary structure but lie close together in the still unknown tertiary structure. Chimera and site-directed mutagenesis studies suggest the involvement of both overlapping and separate domains in the interaction with substrates and blockers, whereas recent findings with involvement of both overlapping and separate domains in the interaction with substrates nad blockers, binding of blockers such as cocaine. The dopamine transporter can also operate in reverse, i.e. in an efflux mode, and recent mutagenesis experiments show different structural requirements for inward and outward transport. Strong evidence for dopamine transporter domains selectively influencing binding of dopamine or cocaine analogs has not yet emerged, although the development of a cocaine antagonist at the level of the transporter remains a possibility. (C) 2000 Elsevier Science B.V. All rights reserved.