Genetic Control of Glutamate Receptor Function

谷氨酸受体功能的遗传控制

基本信息

批准号：
7341062
负责人：
RAYMOND J DINGLEDINE
金额：
$ 33.55万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-12-01 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341062
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions AMPA Receptors Address Adult Agonist Antibodies Brain Calcium Chromatin Structure Complex Cordycepin Data Dendritic Spines Dominant-Negative Mutation Down-Regulation Elements Excitatory Synapse Genes Genetic GluR2 subunit AMPA receptor Glutamate Receptor Internal Ribosome Entry Site Interneurons Ischemia Lasers Learning Ligation MAP Kinase Gene MAP Kinase Signaling Pathways Mediating Messenger RNA Mitogen-Activated Protein Kinases N-Methyl-D-Aspartate Receptors Neuraxis Neurons Oocytes Pathway interactions Phase Phenotype Physiological Polyadenylation Polymerase Chain Reaction Population Property Protein Biosynthesis Protein Overexpression Proteins RNA Rate Receptor Gene Regulation Regulatory Element Relative (related person)Reporter Repression Response Elements Seizures Signal Transduction Site Stimulus Structure Synapses Synaptic Receptors Synaptic plasticity System Testing Transcript Transgenic Mice Translating Translational Regulation Translations Untranslated Regions Work Xenopus oocyte alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid amino 3 hydroxy 5 methylisoxazole 4 propionate base cell injury genetic manipulation mutant postsynaptic promoter receptor receptor function research study response

项目摘要

DESCRIPTION (provided by applicant): The abundance of GluR2 mRNA relative to other AMPA receptor subunit mRNAs is highly variable in many GABAergic interneurons, which endows them with a wide spectrum of AMPA receptor properties. GluR2 mRNA and protein levels decline following intense seizure activity or transient ischemia in certain vulnerable neuron populations before clear histological signs of cell damage, raising the possibility that larger synaptic currents or excess calcium entry through newly synthesized GluR2-deficient AMPA synaptic receptors contributes to the later phase of neuron damage. There is evidence for activity-dependent local dendritic translation of GluR2 mRNA, and for postsynaptic GluR2 translation following LTP stimuli. All of these findings indicate that the mechanisms responsible for moderate changes in GluR2 expression - developmentally, during synaptic plasticity, and after seizures or traumatic insult in the adult - are important neuronal regulatory controls governing synaptic phenotype. Work in the current project period has identified specific transcriptional and translational regulatory mechanisms operating on AMPA receptor genes. In the proposed work we intend to test the following hypotheses: i) that translational regulation of GluR2 mRNA requires one or more of the multiple conserved cytoplasmic polyadenylation elements (CPE) or polyadenylation response elements (PRE) resident in the 3'UTR; ii) that MAP kinase pathways exert dual control over translation of GluR2 transcripts; iii) that neuron-dependent transcriptional start site selection influences the form and extent of translational control by 5' and 3'UTR; and iv) that repression of GluR2 expression by seizures requires the RE1 silencer in the GluR2 promoter. Regulation of the physiological properties of glutamate receptor channels at the translational and transcriptional levels should be relevant to the late phase of LTP, learning, and the response to seizures, as well as other situations in which receptor phenotype is remodeled .

描述（由申请人提供）：GluR2 mRNA 相对于其他 AMPA 受体亚基 mRNA 的丰度在许多 GABA 能中间神经元中变化很大，这赋予它们广泛的 AMPA 受体特性。在某些脆弱神经元群体中，在出现明显的细胞损伤组织学迹象之前，GluR2 mRNA和蛋白质水平会随着强烈的癫痫活动或短暂性缺血而下降，这增加了更大的突触电流或通过新合成的缺乏GluR2的AMPA突触受体的过量钙进入导致后来的神经元损伤的可能性。神经元损伤阶段。有证据表明 GluR2 mRNA 的活动依赖性局部树突翻译，以及 LTP 刺激后的突触后 GluR2 翻译。所有这些发现表明，在发育过程中、突触可塑性期间以及成人癫痫或创伤性损伤后，GluR2 表达中度变化的机制是控制突触表型的重要神经元调节控制。当前项目期间的工作已经确定了作用于 AMPA 受体基因的特定转录和翻译调节机制。在拟议的工作中，我们打算测试以下假设：i）GluR2 mRNA 的翻译调节需要驻留在 3'UTR 中的一个或多个保守的细胞质聚腺苷酸化元件（CPE）或多聚腺苷酸化反应元件（PRE）； ii) MAP 激酶途径对 GluR2 转录物的翻译发挥双重控制； iii) 神经元依赖性转录起始位点选择影响 5' 和 3'UTR 翻译控制的形式和程度； iv) 通过癫痫发作抑制 GluR2 表达需要 GluR2 启动子中的 RE1 沉默子。谷氨酸受体通道在翻译和转录水平上的生理特性的调节应该与 LTP 的后期、学习和癫痫反应以及受体表型重塑的其他情况有关。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes.

REST 的转录抑制：将 Sin3A 和组蛋白脱乙酰酶募集到神经元基因。

DOI：
发表时间：
1999-10
期刊：
影响因子：
0
作者：
Huang, Y;Myers, S J;Dingledine, R
通讯作者：
Dingledine, R

Subunit-specific desensitization of heteromeric kainate receptors.

异聚红藻氨酸受体的亚基特异性脱敏。

DOI：
发表时间：
2010-02-15
期刊：
影响因子：
0
作者：
Mott, David D;Rojas, Asheebo;Fisher, Janet L;Dingledine, Raymond J;Benveniste, Morris
通讯作者：
Benveniste, Morris

Translational regulation of GluR2 mRNAs in rat hippocampus by alternative 3' untranslated regions.

大鼠海马中 GluR2 mRNA 通过替代 3 非翻译区的翻译调节。

DOI：
发表时间：
2009-04
期刊：
影响因子：
4.7
作者：
Irier, Hasan A;Shaw, Renee;Lau, Anthony;Feng, Yue;Dingledine, Raymond
通讯作者：
Dingledine, Raymond

Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro.

体内大鼠新皮质细胞和体外分离神经末梢对果糖的摄取和代谢。

DOI：
发表时间：
2015-05
期刊：
影响因子：
4.7
作者：
Hassel, Bjørnar;Elsais, Ahmed;Frøland, Anne;Taubøll, Erik;Gjerstad, Leif;Quan, Yi;Dingledine, Raymond;Rise, Frode
通讯作者：
Rise, Frode

Control of glutamate receptor 2 (GluR2) translational initiation by its alternative 3' untranslated regions.

通过其替代的 3 非翻译区控制谷氨酸受体 2 (GluR2) 翻译起始。