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.

这项建议描述了旨在了解糖尿病发病机制的研究。 神经递质转运体。这些转运体负责 终止突触释放的神经递质的活动。在……里面 此外，5-羟色胺转运体负责积累 外周血细胞(血小板和嗜碱性粒细胞)、胎盘中的5-羟色胺 还有肺。5-羟色胺转运体是 临床上有用的抗抑郁药物，如丙咪嗪和 氟西汀。多巴胺转运体被认为是生理性的 可卡因的目标。安非他明，包括丙二醛和摇头丸(摇头丸)法案 通过逆转这些传输器的正常运行并导致 5-羟色胺、去甲肾上腺素和多巴胺的外流。最近，cDNA克隆 已经分离出了依赖于Na+和C1的家族的编码 转运蛋白包括GABA，甘氨酸，脯氨酸，去甲肾上腺素， 5-羟色胺和多巴胺。我们的长期目标是了解这些 转运蛋白的作用是将其神经递质底物 质膜。在此应用程序中，我们建议检查 运输机的一级结构与其内部结构之间的关系 功能。我们将使用两种方法。第一个是检查 转运蛋白在这一过程中的功能异同 并将转运蛋白之间的序列保守性与 功能相似之处。第二种方法是突变氨基酸。 转运蛋白序列中与给定的 函数，然后检查各种函数的结果 传输器的属性。通过这种结合的方法，我们希望 了解有关这些传输器工作方式的更多信息，并确定 转运蛋白功能所需的特定氨基酸。