Structure and Function of Neurotransmitter Transporters

人类神经系统的功能依赖于数十亿的神经细胞。大量细胞之间的主要交流机制包括化学突触——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受体的特殊连接。为了使这种神经传递循环快速而忠实地重复，神经递质必须被清除或从突触中移除。有大量的治疗药物和各种各样的非法化合物可以调节转运蛋白的功能，包括抗抑郁药、可卡因和安非他明。在大多数化学突触中，递质的清除是由称为转运蛋白的完整膜蛋白完成的。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依赖泵建立的离子梯度来热力学驱动或泵送递质进入邻近细胞；这些蛋白质通常被称为离子偶联同体。在其他情况下，如谷氨酸/胱氨酸交换，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转运蛋白。由于正转运体和反转运体都是高度疏水的整体膜蛋白，用x射线衍射方法研究它们的原子结构是困难的。我建议对神经递质正转运体和反转运体的细菌同源物进行高分辨率晶体学研究，并结合互补的功能研究，开发这些关键转运蛋白功能的分子机制。另外，我提议开始

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.