STRUCTURE AND FUNCTION OF RECEPTORS AND TRANSPORTERS AT CHEMICAL SYNAPSES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该提议涉及三种不同且独特的整合膜蛋白：（1）真核五聚体“Cys环”受体;（2）真核P2 X离子通道;和（3）真核全长离子型谷氨酸受体（iGluR）。 我们正在研究所谓的半胱氨酸环受体的结构和功能，其中烟碱乙酰胆碱受体可能是最知名的例子。 这些五聚体配体门控离子通道在人类生理学中，特别是在神经系统中发挥重要和广泛的作用，并且是广谱治疗剂和情绪改变物质的靶标。 我们有一个真核生物半胱氨酸环受体的晶体，它的分辨率为3.2英寸。 第二个项目的重点是全长P2 X受体。 P2 X受体是一种仅存在于多细胞真核生物中的ATP门控离子通道，在神经系统中发挥重要作用。 去年，我们报道了斑马鱼P2 X4受体在apo封闭状态下的结构。 现在我们的目标是解决其他功能状态下的结构：开放;封闭-脱敏;封闭-拮抗剂结合。这些结构不仅将阐明P2 X受体的机制，而且还可能促进新型治疗剂的开发。 第三个项目涉及谷氨酸门控离子通道晶体的研究，谷氨酸门控离子通道是人类神经系统快速突触传递的关键。 去年，我们还报道了大鼠GluA 2 AMPA敏感受体在拮抗剂结合的封闭状态下的第一个结构。现在，我们的目标是解决受体在多个功能状态，包括激动剂结合，脱敏状态和激动剂结合开放状态的结构。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This proposal involves three different and unique integral membrane proteins: (1) a eukaryotic pentameric 'Cys-loop' receptor; (2) a eukaryotic P2X ion channel; and (3) a eukaryotic, full-length ionotropic glutamate receptor (iGluR). We are studying the structure and function of so-called Cys-loop receptors of which the nicotinic acetylcholine receptor is perhaps the most well known example. These pentameric, ligand-gated ion channels play essential and widespread roles in human physiology, particularly in the nervous system, and are the targets of a broad spectrum of therapeutic agents and mood altering substances. We have crystals of a eukaryotic Cys-loop receptor that diffract to 3.2 ¿ resolution. The second project is focused on full-length P2X receptors. P2X receptors are ATP-gated ion channels that are present only in multicellular eukaryotes and that play key roles in nervous system. Last year we reported the structure of the zebra fish P2X4 receptor in an apo, closed state. Now we aim to solve structures in other functional states: open; closed-desensitized; closed-antagonist bound. These structures will not only shed light on the mechanism of P2X receptors but they may also facilitate the development of novel therapeutic agents. The third project involves studies of crystals of glutamate-gated ion channels, the linchpins of fast synaptic transmission in the human nervous system. Last year we also reported the first structure of the rat GluA2 AMPA-sensitive receptor in an antagonist-bound, closed state. Now we aim to solve the structures of the receptor in multiple functional states, including the agonist-bound, desensitized state and the agonist-bound open state.