NEUROTRANSMITTER TRANSPORT

描述(申请人摘要)： 生物胺转运体负责终止突触 5-羟色胺(5-羟色胺)、多巴胺(DA)和去甲肾上腺素(NE)的作用。他们 是丙咪嗪和百忧解等抗抑郁剂的分子靶点 以及可卡因和安非他明等精神刺激剂。努力 目前针对设计可卡因拮抗剂做出假设 可卡因和生物胺结合部位的接近程度 传送器。这个应用程序描述了旨在绘制 氨基酸残基在生物胺转运体中的位置 参与底物和抑制剂的结合。这些实验将 提供证据来测试目前用于设计可卡因的假设 治疗药物。生物胺转运体使用跨膜离子 驱动神经递质摄取的梯度。化学计量学中的耦合作用 这一过程是每种运输机的特点。这份提案概述了 计划确定DA传输的离子耦合化学计量比和 与去甲肾上腺素和5-羟色胺转运的化学计量学进行比较。突变型 运输者将接受测试，以确定化学计量比如何 不同的转运蛋白取决于不同的氨基酸。 综上所述，本提案中概述的实验是有针对性的 最终目标是了解初选的每个部分是如何 生物胺转运蛋白的序列参与结合 以及底物的转移。

DESCRIPTION (Applicant's Abstract): Biogenic amine transporters are responsible for terminating the synaptic action of serotonin (5-HT), dopamine (DA), and norepinephrine (NE). They are the molecular targets for antidepressants such as imipramine and Prozac as well as for psychostimulants such as cocaine and amphetamines. Efforts currently directed at designing cocaine antagonists make assumptions about the proximity of cocaine and biogenic amine binding sites on the transporter. This application describes experiments designed to map the location of amino acid residues in biogenic amine transporters that are involved with substrate and inhibitor binding. These experiments will provide evidence to test the assumptions now being used to design cocaine treatment medications. Biogenic amine transporters use transmembrane ion gradients to drive neurotransmitter uptake. The coupling stoichiometry for this process is characteristic of each transporter. This proposal outlines plans to determine the ion coupling stoichiometry for DA transport and to compare it with the stoichiometry for NE and 5-HT transport. Mutant transporters will be tested to determine how the stoichiometry of an individual transporter depends on individual amino acids. Taken together, the experiments outlined in this proposal are directed toward the ultimate goal of understanding how each part of the primary sequence of a biogenic amine transport protein participates in the binding and the translocation of substrates.