Mechanisms of CaMKII Binding to GluN2B and its Role in Synaptic Plasticity and Me
CaMKII 与 GluN2B 结合的机制及其在突触可塑性和 Me 中的作用
基本信息
- 批准号:8648004
- 负责人:
- 金额:$ 2.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-12-01 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityBehavioralBindingCalmodulinCell DeathCell physiologyCellsCo-ImmunoprecipitationsComplexDataDiseaseDissociationDoseDrug AddictionEpilepsyGlutamate ReceptorHippocampus (Brain)ImpairmentIn VitroLeadLearningLong-Term PotentiationMaintenanceMeasurementMeasuresMediatingMediationMediator of activation proteinMemoryMolecularMusN-MethylaspartateNeuronsNucleotidesPeptidesPharmacologyPhasePhosphorylationPhosphotransferasesPhysiologicalPlayProcessProteinsResolutionRoleSignal TransductionSiteSliceSpecificityStaurosporineStimulusStrokeSynapsesSynaptic plasticitySystemTestingTherapeuticTrainingWild Type Mouseaddictioncalmodulin-dependent protein kinase IIclinically relevantdensitygenetic manipulationin vitro Assayinformation gatheringinhibitor/antagonistinterestlong term memorymemory acquisitionmemory retentionmorris water mazemouse modelnervous system disorderpreventprotein functionpublic health relevanceresponse
项目摘要
DESCRIPTION (provided by applicant):
Long-term potentiation (LTP) is a cellular process important in the mediation of synaptic strength, which is thought to underlie learning and memory. Ca2+/Calmodulin-dependent protein kinase II (CaMKII) and the NMDA-type glutamate receptor subunit 2B (GluN2B) are two important proteins in LTP. The interaction between the proteins is additionally required for normal induction of LTP. The functions of these proteins have been associated with a number of neurological disorders such as epilepsy, stroke, and addiction. Of particular interest is the role f CaMKII in the maintenance phase of LTP. While this protein has a well- defined role in LTP induction, its function in maintenance is unclear. Many studies have demonstrated that enzymatic activity of CaMKII is not required; however, it has recently been suggested that a structural interaction between CaMKII and the NMDAR-complex may have an important role. It is further speculated that CaMKII-GluN2B binding specifically mediates this effect due to a few key aspects of that interaction. Namely, translocation of CaMKII to GluN2B is induced by LTP stimuli, the interaction maintains CaMKII in an active state after stimuli have subsided, and binding also persists post-stimuli. Therefore, GluN2B maintains CaMKII activity and localization after LTP induction, providing a theoretical explanation for the structural role of CaMKII in LTP maintenance. The current study will further investigate the role of CaMKII-GluN2B binding in LTP maintenance in three aims, specifically hypothesizing that the interaction is required for maintenance as well as the behavioral correlate of that process, i.e. memory storage. Aim 1: How does enzymatic activity of CaMKII effect GluN2B binding? Hypothesis: Enzymatic activity of CaMKII is not required for its interaction with GluN2B. Aim will be addressed using two ATP competitive inhibitors of CaMKII, H7 and staurosporine (ST), using the following approaches: (i) measurement of CaMKII-GluN2B binding in an in vitro assay using purified proteins, and (ii) stimulus-induced translocation of CaMKII to GluN2B in heterologous cellular expression systems and in primary neuron cultures. Aim 2: Is LTP maintenance mediated by the persistent association of CaMKII-GluN2B? Hypothesis: Sustained binding of CaMKII to GluN2B after LTP stimuli is required for LTP maintenance. Aim will be addressed by comparing wild type (WT) and CaMKII-GluN2B binding incompetent knockin mice (KI) with respect to (i) reduction in LTP maintenance measured under the treatment with the CaMKII inhibitor tatCN21 and (ii) reduction in CaMKII-NMDAR complexes under tatCN21 treatment. Aim 3: Are CaMKII-NMDAR complexes required for memory consolidation? Hypothesis: Memory storage is dependent on the persistent association of CaMKII-NMDAR-complexes. Aim will be addressed by training WT mice on the Morris Water Maze (MWM) and then testing their memory retention after administration of tatCN21, expecting that the inhibitor will reverse memory consolidation.
描述(由申请人提供):
长时程增强 (LTP) 是调节突触强度的重要细胞过程,被认为是学习和记忆的基础。 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 和 NMDA 型谷氨酸受体亚基 2B (GluN2B) 是 LTP 中的两个重要蛋白。蛋白质之间的相互作用对于 LTP 的正常诱导也是必需的。这些蛋白质的功能与许多神经系统疾病有关,例如癫痫、中风和成瘾。特别令人感兴趣的是 f CaMKII 在 LTP 维持阶段的作用。虽然该蛋白在 LTP 诱导中具有明确的作用,但其在维持中的功能尚不清楚。许多研究表明,CaMKII 的酶活性不是必需的;然而,最近有人提出,CaMKII 和 NMDAR 复合物之间的结构相互作用可能具有重要作用。进一步推测,由于该相互作用的几个关键方面,CaMKII-GluN2B 结合特异性介导了这种效应。即,CaMKII 向 GluN2B 的易位是由 LTP 刺激诱导的,这种相互作用在刺激消退后使 CaMKII 保持在活性状态,并且刺激后结合也持续存在。因此,GluN2B在LTP诱导后维持CaMKII活性和定位,为CaMKII在LTP维持中的结构作用提供了理论解释。目前的研究将进一步研究 CaMKII-GluN2B 结合在 LTP 维持中的三个目标的作用,具体假设该相互作用是维持以及该过程的行为相关性所必需的,即记忆存储。目标 1:CaMKII 的酶活性如何影响 GluN2B 结合?假设:CaMKII 的酶活性并不是其与 GluN2B 相互作用所必需的。将使用 CaMKII、H7 和星形孢菌素 (ST) 的两种 ATP 竞争性抑制剂来实现这一目标,采用以下方法:(i) 使用纯化蛋白在体外测定中测量 CaMKII-GluN2B 结合,以及 (ii) 在异源细胞表达系统和原代神经元培养物中刺激诱导 CaMKII 易位为 GluN2B。目标 2:LTP 维持是由 CaMKII-GluN2B 的持续结合介导的吗?假设:LTP 刺激后 CaMKII 与 GluN2B 的持续结合是 LTP 维持所必需的。将通过比较野生型 (WT) 和 CaMKII-GluN2B 结合无能的敲入小鼠 (KI) 来解决以下问题:(i) 在 CaMKII 抑制剂 tatCN21 治疗下测得的 LTP 维持减少,以及 (ii) 在 tatCN21 治疗下 CaMKII-NMDAR 复合物减少。目标 3:记忆巩固是否需要 CaMKII-NMDAR 复合物?假设:记忆存储依赖于 CaMKII-NMDAR 复合物的持久关联。该目标将通过在莫里斯水迷宫 (MWM) 上训练 WT 小鼠,然后在给予 tatCN21 后测试它们的记忆保留情况来实现,期望抑制剂能够逆转记忆巩固。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Kelsey Marie Barcomb其他文献
Kelsey Marie Barcomb的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Kelsey Marie Barcomb', 18)}}的其他基金
Circuit Specific Effects of Morphine on VTA Inhibitory Neuroplasticity
吗啡对 VTA 抑制性神经可塑性的电路特异性影响
- 批准号:
9326386 - 财政年份:2017
- 资助金额:
$ 2.82万 - 项目类别:
Mechanisms of CaMKII Binding to GluN2B and its Role in Synaptic Plasticity and Me
CaMKII 与 GluN2B 结合的机制及其在突触可塑性和 Me 中的作用
- 批准号:
8758663 - 财政年份:2013
- 资助金额:
$ 2.82万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 2.82万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 2.82万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 2.82万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 2.82万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 2.82万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 2.82万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 2.82万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 2.82万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 2.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 2.82万 - 项目类别:
Studentship














{{item.name}}会员




