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

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):

项目成果

期刊论文数量(0)
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Kelsey Marie Barcomb其他文献

Kelsey Marie Barcomb的其他文献

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{{ 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:

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