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从神经元释放后多巴胺，去甲肾上腺素和5-羟色胺的再摄取和回收。质膜生物胺转运蛋白转运蛋白属于Na+的大家族，以及用于神经递质和氨基酸的Cl-依赖性转运蛋白。通过抗抑郁药或可卡因等物质对生物胺转运蛋白抑制具有深远的行为影响，就像其自然底物和苯丙胺衍生物之间的转运蛋白介导的交换一样。特别是，5-羟色胺转运蛋白转运蛋白转运蛋白转运蛋白对可卡因和抗抑郁药（如丙咪嗪和氟西汀（Prozac））的抑制作用，并将细胞内的5-羟色胺（5-羟基胰素胺，5-HT）与外部的半甲苯和其类似物交换为3,4-4-甲基化的3,4-4--被称为“摇头丸”。尽管在理解SERT催化的反应及其耦合到Na+，Cl-和K+离子方面已经取得了很多进展，但基本机制仍然是一个假设，即转运蛋白包含一个结合位点，可交替获得细胞内和细胞外培养基。最近，高分辨率的晶体结构已用于SERT的原用同源物。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。该应用将检查结构模型的预测，并将使用该模型来研究5-羟色胺转运的机理。