MECHANISM OF NMDA REGULATION OF MGLUR5 FUNCTION

NMDA 调控 MGLUR5 功能的机制

• 批准号: 2421327
• 负责人: SUDARKODI ALAGARSAMY
• 金额: $ 2.96万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2421327
• 关键词: NMDA receptors; Xenopus oocyte; animal genetic material tag; enzyme activity; excitatory aminoacid; gene mutation; glutamate receptor; hippocampus; laboratory rat; neuropharmacology; phosphatase inhibitor; phosphoprotein phosphatase; protein kinase C; protein structure function; pyramidal cells; receptor coupling; receptor expression; site directed mutagenesis

Glutamate is the major excitatory neurotransmitter in the hippocampus and seems to be involved in the many normal and pathological processes that occur in this area. Therefore, understanding mechanisms of glutamate action could be important to understanding both normal and pathologic hippocampal functions. Glutamate acts on ionotropic (iGluRs), and metabotropic (mGluRs) glutamate receptors. Activation of mGluRs, possibly mGluR5, can potentiate the effects of NMDA receptors, an iGluR, in the hippocampus. Interestingly, responses thought to be mediated by mGluR5 can be potentiated by the activation of NMDA receptors.This reciprocal regulation between MGluRs5 and NMDA receptors could play an important role in regulating forms of hippocampal synaptic plasticity and could contribute to pathological responses seen in the hippocampus. Several studies have focused on mechanisms of mGluR-activated chant in NMDA receptor function but, little is known about the mechanisms by which NMDA receptor activation might potentiate mGluR-mediated responses. Previous studies have shown that mGluR5 is rapidly desensitized by a protein kinase C (PKC)-dependent mechanism, possibly by phosphorylation of a serine residue on mGluR5. Our preliminary studies that suggest that activation of NMDA receptors may reverse agonist-induced desensitization of mGluR5. These data led us to postulate that NMDA receptor activation potentiates mGluR5-mediated responses by activation of a phosphatase and dephosphorylation of the site on mGluR5 involved in desensitization of this receptor. We propose a series of studies employing a combination of electrophysiology, immunology and molecular biology to rigorously test this hypothesis.

谷氨酸是海马和 似乎参与了许多正常和病理过程 发生在这个区域。因此，了解谷氨酸的机制 动作对于理解正常和病理可能很重要 海马功能。谷氨酸作用于离子（iglurs）和 代谢性（mglurs）谷氨酸受体。激活mglurs，可能 mglur5，可以增强NMDA受体（iglur）的影响 海马。有趣的是，被认为是由mglur5介导的反应可以 通过NMDA受体的激活来增强。 MGLURS5和NMDA受体之间的调节可以发挥重要作用 在调节海马突触可塑性的形式中，可以 有助于海马中看到的病理反应。一些 研究的重点是NMDA中MGLUR激活唱歌的机制 受体功能，但对NMDA的机制知之甚少 受体激活可能会增强MGLUR介导的反应。以前的 研究表明，mglur5被蛋白激酶迅速脱敏 C（PKC）依赖性机制，可能是通过丝氨酸的磷酸化 mglur5上的残留物。我们的初步研究表明激活 NMDA受体可能会反向激动剂诱导的mglur5脱敏。 这些数据导致我们假设NMDA受体激活增强 MGlUR5介导的反应通过激活磷酸酶和 该位点在MGLUR5上的去磷酸化参与脱敏 这个受体。我们提出了一系列研究，结合了 电生理学，免疫学和分子生物学进行严格测试 这个假设。