Structure and Function of Neurotransmitter Transporters

人类神经系统的功能依赖于数十亿个神经细胞。这一数量庞大的细胞进行通讯的主要机制涉及化学突触--一种特殊的连接，其中一个细胞释放的小分子神经递质结合并激活相邻细胞上的受体。为了让这个神经传递的循环快速而忠实地重复，神经递质必须从突触中清除或去除。有大量的治疗药物和各种各样的非法化合物调节转运功能，包括抗抑郁药、可卡因和安非他明。在大多数化学突触中，传递物质的清除是由称为转运蛋白的膜蛋白完成的。在许多情况下，如谷氨酸、GABA、甘氨酸和生物胺转运蛋白，转运蛋白利用ATP依赖性泵建立的离子梯度，将递质驱动或泵入相邻细胞;这些蛋白质通常被称为离子偶联共转运蛋白。在其他情况下，例如使用谷氨酸/胱氨酸交换器，转运蛋白强制性地将一种底物（谷氨酸）交换为另一种底物（胱氨酸）;这些转运蛋白通常被称为反向转运蛋白。因为同向转运蛋白和反向转运蛋白都是高度疏水的膜蛋白，用X射线衍射方法研究它们的原子结构是困难的。我建议进行高分辨率的晶体学研究的细菌直系同源的神经递质同向转运蛋白和反向转运蛋白，并结合互补的功能研究，开发这些关键的转运蛋白的功能的分子机制。另外，我提议 我的新技术促进了真核神经递质转运蛋白的结构研究 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， 我们还将获得开发新化合物的基本信息，以治疗各种神经系统疾病和紊乱。 相关性（参见说明）： 整合膜转运蛋白从突触中清除神经递质，是两者的靶点 治疗剂，如抗抑郁药，和非法物质，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 human 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 compounds to 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.