METABOTROPIC RECEPTORS AND EXCITOTOXICITY

谷氨酸受体（GluR）介导大部分兴奋性信号 哺乳动物中枢神经系统内的转导。兴奋性毒性， GluR的异常激活导致神经元死亡的过程， 被认为在许多神经系统疾病中发挥作用。的作用 GluR与离子通道连接（“离子型”谷氨酸受体，iGluR） 已经有很好的文献记载了GluR的激活与 第二信使系统（“代谢型”谷氨酸受体，mGluR）可 也影响兴奋性毒性。刺激磷酸肌醇的mGluR 代谢可能会加剧兴奋性毒性，而那些mGluR的， 抑制环AMP产生可减弱兴奋性毒性。而 mGluR影响兴奋性毒性的机制尚不清楚， 可能是mGluR通过改变神经元的功能来影响兴奋性毒性过程， iGluR的功能，例如，通过iGluR的磷酸化。 因此，mGluR提供了一个有吸引力的潜在目标，用于开发 治疗性神经保护剂。 本提案的目的是确定mGluR如何影响 iGluR介导的纹状体兴奋性毒性。三个主要领域将是 研究：1）mGluR激动剂和拮抗剂以及 针对特定mGluR的反义寡核苷酸， 影响体内兴奋性毒性，2）拮抗剂的能力， 激活剂和靶向mGluR连接的 第二信使系统影响体内兴奋性毒性，和3） mGluR受体刺激对iGluR磷酸化的影响。 的 体内兴奋性毒性的测定将包括损伤尺寸分析 在一个充分表征的模型中： 大鼠此外，逆转录-PCR，原位杂交， 受体结合，蛋白质印迹，纹状体细胞培养，和功能 将采用生物化学测定来评估抗 有义寡核苷酸处理以及受体的调节 功能 总之，这些研究旨在阐明重要的 不同类型的GluR之间的相互作用，特别是当它们 兴奋性中毒一旦这些关系被阐明，mGluR 他们本身也可能成为小说发展的合乎逻辑的目标 神经保护剂

Glutamate receptors (GluR's) mediate the majority of excitatory signal transduction within the mammalian central nervous system. Excitotoxicity, a process in which abnormal activation of GluR's leads to neuronal death, is thought to play a role in numerous neurological conditions. The role of GluR's linked to ion channels ("ionotropic" glutamate receptors, iGluR's) in excitotoxicity has been well documented. Activation of GluR's linked to second messenger systems ("metabotropic" glutamate receptors, mGluR's) can also influence excitotoxicity. mGluR's which stimulate phosphoinositide metabolism may exacerbate excitotoxicity, whereas those mGluR's which inhibit cyclic AMP production may attenuate excitotoxicity. While the mechanisms by which mGluR's influence excitotoxicity remain unclear, one possibility is that mGluR's influence excitotoxic processes by altering the function of iGluR's, for example, through phosphorylation of iGluR's. mGluR's thus offer an attractive potential target for the development of therapeutic neuroprotective agents. The objective of this proposal will be to determine how mGluR's affect iGluR-mediated striatal excitotoxicity. Three main areas will be investigated: 1) the ability of mGluR agonists and antagonists as well as of antisense oligonucleotides directed against specific mGluR's to influence in vivo excitotoxicity, 2) the ability of antagonists, activators, and antisense oligonucleotides targeted against mGluR-linked second messenger systems to influence in vivo excitotoxicity, and 3) the effect of mGluR receptor stimulation on iGluR phosphorylation. The determination of in vivo excitotoxicity will involve lesion size analysis in a well characterized model: stereotaxic intrastriatal injection in the rat. In addition, reverse transcription-PCR, in situ hybridization, receptor binding, Western blotting, striatal cell culture, and functional biochemical assays will be employed to assess both the efficacy of anti sense oligonucleotide treatment, as well as regulation of receptor function. Taken together, these studies are designed to shed light on the important interactions between different types of GluR's, especially as they pertain to excitotoxicity. Once the relationships have been elucidated, mGluR's themselves may become logical targets for the development of novel neuroprotective agents.