GLUTAMATE RECEPTOR FUNCTION BY THE NR1 5TH EXON

人们对谷氨酸受体的NMDA亚型产生了浓厚的兴趣 因为它在发育、突触传递、记忆和 病理情况，如缺血和癫痫。尽管NMDA 受体受许多内源性物质的调节，控制 通过质子的生理浓度实现的受体功能 尤其重要的是，不仅是因为间质的pH值非常高 动态的，但也是因为胞外酸化 伴随着缺血和癫痫发作。PH值的这些扰动可能会 作为负反馈抑制NMDA受体功能，从而限制 缺血时癫痫发作持续时间或谷氨酸介导的损伤。我的 初步研究表明，NR1基因的第5个外显子 亚基使受体对质子不敏感，这种效应可以 被内源性多胺模仿。这一发现提供了一个机会来 从结构角度探讨质子对NMDA受体功能的控制 另外还增加了不同剪接变体的可能性 NMDA受体可能与血管内皮细胞的选择性易感性有关 中枢结构与缺血引起的损伤或癫痫发作有关。这个 该项目的长期目标是确定结构和 功能水平NR1第5外显子如何控制正常和 病态的情况。五个主要目标是： (1)确定NR1第5外显子内的结构决定因素 控制质子抑制。 (2)在生物物理水平上确定NR1第5外显子是如何控制的 感受器对质子的敏感性。 (3)鉴定调节NMDA受体质子的化合物 敏感性，并确定这些化合物是否在 类似于第5外显子的方式。 (4)研究重组人的质子敏感性之间的联系 NMDA受体剪接变异体及其细胞毒活性。 (5)确定第5外显子是否在 中枢神经系统。 这些实验将有助于在结构、解剖学和 功能水平第五外显子如何影响受体功能。在……里面 此外，这些实验将有助于定义一个重要的监管 NMDA受体上的位置，并识别在该位置起作用的化合物。

Intense interest has focused on the NMDA subtype of glutamate receptor because of its roles in development, synaptic transmission, memory, and pathological situations such as ischemia and epilepsy. Although NMDA receptors are modulated by many endogenous substances, the control of receptor function by physiological concentrations of protons is particularly important, not only because the interstitial pH is highly dynamic, but also because of the extracellular acidification that accompanies ischemia and seizures. These perturbations in pH could serve as negative feedback to inhibit NMDA receptor function, and thereby limit seizure duration or glutamate-mediated damage during ischemia. My preliminary studies have shown that the 5th alternative exon of the NR1 subunit renders receptors proton-insensitive, and this effect can be mimicked by endogenous polyamines. This finding provides an opportunity to approach proton control of NMDA receptor function in structural terms, and additionally raises the possibility that the different splice variants of the NMDA receptor might be related to the selective vulnerability of central structures to ischemia-induced damage or seizure initiation. The long-term objective of this project is to determine at the structural and functional level how the 5th NR1 exon controls receptors in normal and pathological situations. The five main goals are: (1) To identify the structural determinants within the NR1 5th exon that control proton inhibition. (2) To determine at the biophysical level how the NR1 5th exon controls the receptor's proton sensitivity. (3) To identify compounds that modulate the NMDA receptor's proton sensitivity, and determine whether these compounds exert their effects in a manner similar to the 5th exon. (4) To investigate the link between the proton sensitivity of recombinant NMDA receptor splice variants and their cytotoxic potential. (5) To determine whether the 5th exon is differentially expressed in the central nervous system. These experiments will help to explain at the structural, anatomical, and functional levels how the 5th exon influences receptor function. In addition, these experiments will help to define an important regulatory site on the NMDA receptor, and identify compounds that act at that site.