Properties of AMPA and Kainate receptors

这项研究的长期目标是识别和了解突触谷氨酸受体被激活时发生的分子事件。在中枢神经系统（CNS）中传递的大多数兴奋性信息是由谷氨酸受体的激活介导的。因此，谷氨酸受体对于包括学习和记忆在内的许多神经功能是关键的，但也与急性和慢性神经障碍如癫痫和缺血诱导的神经元损伤相关。 在过去的十年中，谷氨酸受体已被确定为开发治疗相关化合物的靶点。 然而，尽管近年来花费了大量的时间、精力和经济成本，但很少有药物显示出临床应用的前景。 最近，第一个晶体结构的激动剂结合结构域的AMPA受体，谷氨酸受体亚型，已获得。 尽管未来的药物开发将受益于晶体结构的原子分辨率，但AMPA受体的动态三维模型还需要进一步了解导致和控制AMPA受体离子通道打开和关闭的事件。本提案中的研究将侧重于观察到通过AMPA受体孔区域（渗透）的离子流与激动剂结合（门控）引发的转导事件相互作用。 这一发现以前没有记录，表明AMPA受体的渗透和门控是耦合的。 将在不同离子条件下研究重组和遗传修饰AMPA受体的单通道和宏观测量，以表征这一观察结果。 拟议的研究将提供AMPA受体的两种门控模式的基本操作信息;失活和脱敏，塑造中枢神经系统兴奋信号的时间进程。 据信，可用于治疗阿尔茨海默病的记忆和认知增强药物可延长AMPA受体的失活和脱敏。 实验将研究孔的性质的变化是否反映AMPA受体的每个门控模式的减慢。

The long-term objective of this research is to identify and understand the molecular events that occur when synaptic glutamate receptors are activated. The majority of excitatory information that is transmitted in the central nervous system (CNS) is mediated by the activation of glutamate receptors. Consequently, glutamate receptors are pivotal for numerous neurological functions including learning and memory but are also associated with acute and chronic nervous disorders such as epilepsy and ischemia-induced neuronal injury. Within the last decade, glutamate receptors have been identified as targets for the development of therapeutically relevant compounds. However, despite the considerable time, effort and financial cost that have been exacted in recent years, few drugs show promise for clinical use. Recently, the first crystal structure of the agonist-binding domain of the AMPA receptor, a glutamate receptor subtype, has been obtained. Although, future drug development will benefit from the atomic resolution of crystal structures, a dynamic, three-dimensional model of the AMPA receptor will also require further insight into the events that lead to and control the opening and closing of the AMPA receptor ion-channel. The research in this proposal will focus on the observation that ion flow through the pore region (permeation) of AMPA receptors interacts with the transduction events that are initiated by agonist binding (gating). This finding has not been documented previously and suggests that permeation and gating of AMPA receptors are coupled. Single channel and macroscopic measurements of recombinant and genetically modified AMPA receptors will be studied in different ionic conditions to characterize this observation. The proposed research will provide basic operational information on two gating modes of AMPA receptors; deactivation and desensitization that shape the time course of excitatory signals in the CNS. Memory- and cognition-enhancing drugs that may be used in the treatment of Alzheimer's disease are believed to prolong deactivation and desensitization of AMPA receptors. Experiments will investigate if changes in the properties of the pore reflect the slowing of each gating mode of the AMPA receptor.