STRUCTURE AND FUNCTION OF RECEPTORS AND TRANSPORTERS AT CHEMICAL SYNAPSES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这一建议涉及三种不同和独特的完整膜蛋白：(1)真核五聚体‘Cys-loop’受体；(2)真核P2X离子通道；(3)真核全长离子型谷氨酸受体(IGluR)。 我们正在研究所谓的Cys-loop受体的结构和功能，烟碱型乙酰胆碱受体可能是最著名的例子。这些五聚体、配体门控离子通道在人类生理学中发挥着重要而广泛的作用，特别是在神经系统中，并且是广泛的治疗剂和情绪改变物质的靶标。我们有一个真核细胞环状受体的晶体，它的衍射率可达3.2？ 第二个项目的重点是全长的P2X受体。P2X受体是一种ATP门控离子通道，仅存在于多细胞真核生物中，在神经系统中起着关键作用。去年，我们报道了斑马鱼P2X4受体在关闭状态下的结构。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-拮抗结合。这些结构不仅有助于阐明P2X受体的作用机制，还可能促进新型治疗药物的开发。 第三个项目涉及对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中快速突触传递的关键。去年，我们还报道了大鼠GluA2 AMPA敏感受体的第一个结构，处于拮抗剂结合的关闭状态。现在我们的目标是解决受体在多种功能状态下的结构，包括激动剂结合、脱敏状态和激动剂结合开放状态。

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.