Ion and Biogenic Amine Transport Mechanism

离子和生物胺传输机制

• 批准号: 7600503
• 负责人: GARY W RUDNICK
• 金额: $ 32.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-12-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600503
• 关键词: Amino Acid Neurotransmitters; Amphetamines; Antidepressive Agents; Behavioral; Binding; Binding Sites; Biogenic Amines; Cell membrane; Cocaine; Complement component C1s; Coupling; Cytoplasm; Dopamine; Face; Family; Fluoxetine; Goals; Homologous Gene; Imipramine; Ions; Learning; Leucine; Light; Measurement; Mediating; Membrane; Modeling; Motion; Movement; Neurons; Neurotransmitters; Norepinephrine; Pathway interactions; Pharmaceutical Preparations; Property; Proteins; Prozac; Publications; Reaction; Recycling; Resolution; Series; Serotonin; Site; Structural Models; Structure; Synaptic Cleft; analog; design; ecstasy; extracellular; research study; reuptake; serotonin transporter

DESCRIPTION (provided by applicant): Biogenic amine transporters are responsible for the reuptake and recycling of dopamine, norepinephrine and serotonin after their release from neurons. Plasma membrane biogenic amine transporters belong to a large family of Na+ and Cl- dependent transporters for neurotransmitters and amino acids. Inhibition of biogenic amine transporters by substances such as antidepressants or cocaine has profound behavioral effects, as does exchange mediated by the transporters between their natural substrate and amphetamine derivatives. In particular, the serotonin transporter (SERT) is sensitive to inhibition by cocaine and antidepressant drugs like imipramine and fluoxetine (Prozac), and exchanges intracellular serotonin (5- hydroxytryptamine, 5-HT) with external amphetamine and its analogs such as 3,4- methylenedioxymethamphetamine (MDMA), also known as "ecstasy". Although much progress has been made in understanding the reaction catalyzed by SERT and its coupling to Na+, Cl- and K+ ions, the fundamental mechanism remains only a hypothesis that the transporter contains a binding site with alternating access to intracellular and extracellular media. Recently, a high resolution crystal structure has become available for a prokaryotic homologue of SERT. This structure provides a model for experiments designed to understand mechanistic and structural properties of mammalian neurotransmitter transporters. This application will examine the predictions of the structural model and will use that model to investigate the mechanism of serotonin transport.

描述（由申请人提供）：生物胺转运蛋白负责多巴胺、去甲肾上腺素和血清素从神经元释放后的再摄取和再循环。质膜生物胺转运蛋白属于依赖于 Na+ 和 Cl 的神经递质和氨基酸转运蛋白大家族。抗抑郁药或可卡因等物质对生物胺转运蛋白的抑制具有深远的行为影响，转运蛋白介导的天然底物与安非他明衍生物之间的交换也是如此。特别是，血清素转运蛋白（SERT）对可卡因和抗抑郁药物如丙咪嗪和氟西汀（百忧解）的抑制敏感，并与外部安非他明及其类似物（如3,4）交换细胞内血清素（5-羟色胺，5-HT） - 亚甲二氧基甲基苯丙胺（MDMA），也称为“摇头丸”。尽管在理解 SERT 催化的反应及其与 Na+、Cl- 和 K+ 离子的偶联方面已经取得了很大进展，但基本机制仍然只是一个假设，即转运蛋白包含一个可以交替进入细胞内和细胞外介质的结合位点。最近，SERT 的原核同系物的高分辨率晶体结构已经可用。该结构为旨在了解哺乳动物神经递质转运蛋白的机械和结构特性的实验提供了模型。该应用程序将检查结构模型的预测，并将使用该模型来研究血清素运输的机制。