NEUROTRANSMITTER TRANSPORT

神经递质运输

• 批准号: 2120685
• 负责人: GARY W RUDNICK
• 金额: $ 18.11万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2120685
• 关键词: alternatives to animals in research; chloride channels; complementary DNA; dopamine; ion transport; laboratory rabbit; membrane permeability; molecular cloning; mutant; nerve endings; neuropharmacology; neurotransmitter transport; norepinephrine; polymerase chain reaction; potassium channel; protein sequence; protein structure function; receptor coupling; sodium channel; stoichiometry; toad; transfection

This proposal describes studies designed to understand the mechanism of neurotransmitter transporters. These transporters are responsible for terminating the action of neurotransmitters released at synapses. In addition, the serotonin transporter is responsible for accumulation of serotonin in peripheral blood cells (platelets and basophils), placenta and lung. The serotonin transporter is the biological target for clinically useful antidepressant drugs, such as imipramine and fluoxetine. the dopamine transporter is believed to be the physiological target for cocaine. Amphetamines, including MDA and MDMA (ecstasy) act by reversing the normal operation of these transporters and causing efflux of serotonin, norepinephrine, and dopamine. Recently, cDNA clones have been isolated which code for a family of Na+ and C1- dependent transporters including those for GABA, glycine, proline, norepinephrine, serotonin and dopamine. Our long range goal is to understand how these transporters work as they move their neurotransmitter substrate across the plasma membrane. In this application, we propose to examine the relationship between the primary structure of the transporter and its function. We will use two approaches. The first is to examine the functional similarities and differences between transporters in this family, and to correlate sequence conservation between transporters with functional similarities. The second approach is to mutate amino acid residues in the transporter sequence that are correlated with a given function and then examine the consequences for various functional properties of the transporter. by this coupled approach we expect to learn more about the way these transporters work and also to identify specific amino acids required for transporter function.

该提案描述了旨在理解机制的研究 神经递质转运蛋白。 这些运输商负责 终止突触释放的神经递质的作用。 在 此外，血清素转运蛋白负责积累 外周血细胞（血小板和嗜碱性粒细胞）、胎盘中的血清素 和肺。 血清素转运蛋白是 临床上有用的抗抑郁药物，例如丙咪嗪和 氟西汀。 多巴胺转运蛋白被认为是生理学 可卡因的目标。 安非他明，包括 MDA 和 MDMA（摇头丸）法案 通过逆转这些运输机的正常运行并导致 血清素、去甲肾上腺素和多巴胺的流出。 最近，cDNA克隆 已分离出 Na+ 和 C1 依赖性家族的代码 转运蛋白，包括 GABA、甘氨酸、脯氨酸、去甲肾上腺素、 血清素和多巴胺。 我们的长期目标是了解这些 转运蛋白在移动神经递质底物时发挥作用 质膜。 在本申请中，我们建议检查 转运体的一级结构与其自身的关系 功能。 我们将使用两种方法。 首先是检查 转运蛋白之间的功能异同 家族，并将转运蛋白之间的序列保守性与 功能上的相似之处。 第二种方法是改变氨基酸 转运蛋白序列中与给定相关的残基 函数，然后检查各种函数的后果 运输者的属性。 通过这种耦合方法，我们期望 了解更多关于这些运输工具的工作方式并识别 转运蛋白功能所需的特定氨基酸。