Structure and Function of Neurotransmitter Transporters

浑南神经系统的功能依赖于数十亿个神经细胞。主要机制 这些大量的细胞通过化学突触进行交流--这种特殊的连接 一个细胞释放的小分子神经递质与相邻细胞上的受体结合并激活。 为了让这一神经传递循环迅速而忠实地重复，神经递质必须 从突触中清除或移除。有大量的治疗药物和各种各样的非法药物 调节转运蛋白功能的化合物，包括抗抑郁剂、可卡因和苯丙胺。在… 大多数化学突触，递质的移除是由称为 传送者。在许多情况下，例如谷氨酸、GABA、甘氨酸和生物胺转运体， 转运蛋白利用依赖于ATP的泵建立的离子梯度来热力学 驱动或泵入相邻细胞的递质；这些蛋白质通常被称为离子偶联 象征者。在其他情况下，例如谷氨酸/半胱氨酸交换器，转运蛋白 必须用一种底物(谷氨酸)交换另一种底物(胱氨酸)；这些转运蛋白通常是 被称为反向转运蛋白。因为共转运蛋白和反转运蛋白都是高度疏水的整体 对于膜蛋白，用X射线衍射法研究其原子结构已被证明是困难的。我 建议开展神经递质细菌直系物的高分辨率结晶学研究 共转运体和反向转运体，并结合免费的功能研究，开发分子 这些关键转运蛋白的功能机制。此外，我建议开始 我所开发的新技术有助于真核神经递质转运体的结构研究 实验室。通过完成拟议的研究，我们不仅将了解这些蛋白质的功能，而且 我们还将掌握开发新化合物的基本信息，以进行广泛的治疗 神经系统疾病和障碍。 相关性(请参阅说明)： 整合膜转运蛋白从突触中移除神经递质，是两者的靶标。 治疗药物，如抗抑郁剂，以及非法物质，如可卡因。这项工作旨在 确定这些重要转运蛋白的分子结构和功能。

The function of the hunnan nervous system is dependent upon billions of nerve cells. A primary mechanism by which this vast number of cells communicates involves chemical synapses - specialized junctions where a small molecule neurotransmitter released by one cell binds to and activates receptors on an adjacent cell. In order for this cycle of neurotransmission to rapidly and faithfully repeat, the neurotransmitter must be cleared or removed from synapses. There are a large number of therapeutic drugs and a wide array of illicit compounds that modulate transporter function, including antidepressants, cocaine and amphetamines. At most chemical synapses, the removal of transmitter is accomplished by integral membrane proteins called transporters. In many cases, such as with glutamate, GABA, glycine and the biogenic amine transporters, the transporter proteins harness ion gradients established by ATP-dependent pumps to thermodynamically drive or pump transmitter into adjacent cells; these proteins are commonly referred to as ion-coupled symporters. In other cases, such as with the glutamate/cystine exchanger, the transporter protein obligatorily exchanges one substrate (glutamate) for another (cystine); these transporters are generally referred to as antiporters. Because both symporters and antiporters are highly hydrophobic integral membrane proteins, studies of their atomic structures by x-ray diffraction methods have proven difficult. I propose to carry out high resolution crystallographic studies of bacterial orthologs of neurotransmitter symporters and antiporters and, in combination with complimentary functional studies, develop molecular mechanisms for the function of these crucial transporter proteins. In addition, I propose to commence structural studies of eukaryotic neurotransmitter transporters facilitated by new technology developed in my laboratory. By accomplishing the proposed studies, we will not only learn how these proteins function, but we will also have the fundamental information for the development of new compoundsto treat a wide range of neurological diseases and disorders. RELEVANCE (See instructions): Integral membrane transport proteins remove neurotransmitters from synapses and are the targets of both therapeutic agents, such as antidepressants, and illicit substances, such as cocaine. This work aims to determine the molecular structure and function of these important transporter proteins.