NEUROTRANSMITTER TRANSPORT

该提案描述了旨在了解 神经递质转运蛋白 这些传送者负责 终止突触释放的神经递质的作用。 在 此外，5-羟色胺转运蛋白负责积累 外周血细胞（血小板和嗜碱性粒细胞）中的5-羟色胺，胎盘 和肺 血清素转运体是 临床上有用的抗抑郁药物，如丙咪嗪和 氟西汀。 多巴胺转运蛋白被认为是 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操作， 血清素去甲肾上腺素和多巴胺的流出。 最近，cDNA克隆 已经分离出编码Na+和C1-依赖性的家族， 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 转运蛋白的工作原理是将神经递质底物 质膜。 在本申请中，我们建议审查 转运蛋白的一级结构与其 功能 我们将使用两种方法。 第一，检查 在这一过程中， 家族，并将转运蛋白之间的序列保守性与 功能相似性。 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 运输机的特性。 通过这种结合的方法，我们希望 了解更多关于这些传输器的工作方式， 转运蛋白功能所需的特定氨基酸。

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.