Molecular Structure of CNS Postsynaptic Densities

中枢神经系统突触后密度的分子结构

基本信息

批准号：
7340750
负责人：
MARY B KENNEDY
金额：
$ 31.32万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
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：
1997-08-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7340750
关键词：
AMPA Receptors Actins Adenosine Adrenergic Receptor Agonist Alzheimer&apos s Disease Amprenavir Apoptosis Apoptotic Biochemical Biochemical Pathway Biological Assay Brain Brain-Derived Neurotrophic Factor Calcineurin Cell Death Chromosome Pairing Class Cleaved cell Complex Cytoskeleton Detection Disease Endocytosis Enzymes Ephrin B Receptor Epilepsy Excision Exocytosis Family Family member GTPase-Activating Proteins Ganciclovir Glutamates Grant Growth Factor Receptors Guanosine Triphosphate Phosphohydrolases Hand Insulin Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor JNK-activating protein kinase Knock-out Lead Link MAPK14 gene Mediating Membrane Mental Depression Mitochondria Molecular Molecular Structure Morphology Mus Mutant Strains Mice N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Degeneration Neurodegenerative Disorders Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Pathway interactions Phosphorylation Protein phosphatase Psyche structure Receptor Activation Regulation Regulatory Pathway Relative (related person)Reporting Research Personnel Schizophrenia Series Shapes Signal Transduction Site Synapses Synaptic Transmission Testing Time Tissues Vertebral column Work calmodulin-dependent protein kinase II caspase-8 caspase-9 density design dihydroxyphenylethylene glycol insight neurological pathology neuron apoptosis postsynaptic protein activation receptor research study response synaptogenesis

项目摘要

Derangements in synaptic transmission are part of the pathology of neurological and mental diseases including epilepsy, schizophrenia, depression, and Alzheimer's disease. We are studying the molecular mechanisms underlying regulation of synaptic transmission. In previous years, we have focused on the organization of biochemical regulatory pathways located in the postsynaptic density of glutamatergic synapses. In the previous grant period, we found that RasGAP activity of synGAP, a prominent component of the postsynaptic density and a negative regulator of Ras and Rap signaling, is regulated biphasically by the glutamatergic NMDA receptor (NMDAR), CaMKII, and calcineurin. SynGAP may thus modulate activation of Ras by growth factor receptors at synapses, depending on the timing between activation of the NMDAR and activation of the growth factor receptors. We also found that deletion of synGAP results in increased neuronal apoptosis in brains of mutant mice. Our Specific Aims include a series of experiments that will test three hypotheses: 1. SynGAP is a key postsynaptic regulator of Ras and Rap at spine synapses; 2. Biphasic regulation of synGAP by the NMDAR, CaMKII, and calcineurin underlies a form of "coincidence detection" between the NMDAR and other classes of receptors that modulates activation of Ras and/or Rap in the spine; and 3. Derangement of this regulation can shift neuronal biochemical regulatory networks toward initiation of apoptosis. Specifically, we will test; 1) whether activation of NMDARs and synGAP can modulate the level of activation of Ras and ERK by agonists of growth factor receptors including BDNF; and, 2) whether phosphorylation of synGAP by CaMKII changes its RapGAP activity and/or its relative ability to inactivate Ras and Rap. 3) If we find that phosphorylation of synGAP by CaMKII alters its RapGAP activity, we will test whether activation of NMDA receptors in neurons modulates activation of Rap, ERK, and p38 by agonists of receptors that may activate Rap. Finally, 4) We will test the hypothesis that heterozygous and homozygous deletion of synGAP leads to derangements in biochemical pathways that regulate neuronal apoptosis. Alzheimer's disease, and perhaps other neurodegenerative diseases, are believed to begin with relatively subtle dysregulation of synaptic transmission at glutamatergic synapses. Our work may illuminate how synaptic dysregulation can lead eventually to neuronal apoptosis.

突触传递紊乱是神经和精神疾病病理学的一部分包括癫痫、精神分裂症、抑郁症和阿尔茨海默病。我们正在研究分子突触传递调节的潜在机制。前几年，我们重点关注位于谷氨酸能突触后密度的生化调节途径的组织突触。在之前的资助期间，我们发现 synGAP 的 RasGAP 活性是一个突出的组成部分突触后密度的调节因子以及 Ras 和 Rap 信号传导的负调节因子，受到双相调节谷氨酸能 NMDA 受体 (NMDAR)、CaMKII 和钙调神经磷酸酶。 SynGAP 可能因此调节突触处的生长因子受体激活 Ras，具体取决于激活之间的时间 NMDAR 和生长因子受体的激活。我们还发现删除 synGAP 会导致突变小鼠大脑中神经元凋亡增加。我们的具体目标包括一系列实验这将检验三个假设： 1. SynGAP 是脊柱 Ras 和 Rap 的关键突触后调节因子突触； 2. NMDAR、CaMKII 和钙调磷酸酶对 synGAP 的双相调节是一种形式的基础 NMDAR 与调节 Ras 激活的其他类别受体之间的“重合检测” 和/或敲击脊柱； 3. 这种调节的紊乱可以改变神经元生化调节网络走向细胞凋亡的启动。具体来说，我们将测试； 1) 是否激活NMDARs以及 synGAP 可以通过生长因子受体激动剂调节 Ras 和 ERK 的激活水平包括脑源性神经营养因子；以及，2) CaMKII 对 synGAP 的磷酸化是否会改变其 RapGAP 活性和/或其灭活 Ras 和 Rap 的相对能力。 3) 如果我们发现 CaMKII 对 synGAP 的磷酸化改变了其 RapGAP 活性，我们将测试神经元中 NMDA 受体的激活是否调节 Rap、ERK 和 p38 通过可能激活 Rap 的受体激动剂发挥作用。最后，4）我们将检验假设 synGAP 的杂合和纯合缺失会导致生化途径紊乱调节神经细胞凋亡。阿尔茨海默病，也许还有其他神经退行性疾病，据信始于谷氨酸能突触的突触传递相对微妙的失调。我们的工作可能会阐明突触失调如何最终导致神经元凋亡。