CaMKII biophysics and its role in LTP: Undergraduate Supplement

CaMKII 生物物理学及其在 LTP 中的作用：本科生补充材料

基本信息

批准号：
10393305
负责人：
Margaret M Stratton
金额：
$ 1.04万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393305
关键词：
Address Affect Alzheimer&apos s Disease Animals Biochemical Biochemistry Biological Assay Biophysics Biosensor Brain Cell Culture Techniques Cells Cellular biology Data Defect Dendrites Dependence Disease Progression Enzymes Event Frequencies Future Gene Expression Goals Hand Hippocampus (Brain)Holoenzymes In Vitro Learning Length Long-Term Potentiation Maintenance Mammalian Cell Measures Memory Modeling Molecular Monitor Mutation Neurons Pathology Pathway interactions Phosphorylation Phosphotransferases Physiologic pulse Physiological Play Positioning Attribute Process Property Protein Isoforms Proteins Regulation Regulatory Pathway Research Role Signal Pathway Signal Transduction Site Stimulus Structure Synapses Synaptic Transmission System Time Transgenic Mice Traumatic Brain Injury Work biophysical properties calmodulin-dependent protein kinase II experience fascinate improved in vivo long term memory nervous system disorder neurotransmission novel programs protein degradation protein structure recruit shared memory undergraduate student

项目摘要

PROJECT SUMMARY How does a memory outlast the lifetime of the molecule that encodes it? More than two decades ago, Francis Crick had the foresight to speculate that perhaps a multimeric protein could serve as a molecular memory by sharing its activation state with newly synthesized proteins through subunit exchange in order to store a memory for years. Ca2+-calmodulin dependent protein kinase II (CaMKII) was identified as an enzyme that may fit this description. For example, mutation of CaMKII at sites critical for its function results in severe learning and memory defects. CaMKII is activated at a threshold neuronal spike frequency and is crucial to long-term potentiation (LTP). A major obstacle to understanding LTP is the absence of understanding how regulatory pathways recruited during this initial high-frequency stimulus are able to remain persistently active in the face of ongoing protein turnover. Our recent work has shown that CaMKII exchanges subunits between holoenzymes in an activation-dependent manner. Importantly, kinase activity is conferred to unactivated CaMKII holoenzymes by trans-phosphorylation as a consequence of subunit exchange, thereby potentiating the activation signal past the time of protein degradation. This cycle may continue indefinitely. Our work is aimed to further investigate this phenomenon, specifically in respect to its role in LTP. Our major research goals are to: 1) understand the role of the unique biophysical properties of CaMKII (how linker length affects activation, frequency dependence and subunit exchange) that contribute to its potential for being a `memory molecule,' and 2) investigate the properties of CaMKII (such as subunit exchange and changes in gene expression) in cellular systems to determine its physiological role in LTP. These challenging goals require the synthesis of information obtained from the molecular level (protein structure and regulation) to the cellular level (mammalian cell culture) and finally to the animal level (transgenic mice), which will be for future study. Completion of the proposed work will allow us to better address neurologic disease progression as it affects memory, such as pathologies seen in Alzheimer's, dementia, and traumatic brain injury.

项目概要记忆如何比编码它的分子的寿命更长久？二十多年前，弗朗西斯克里克有先见之明，推测多聚蛋白也许可以通过以下方式充当分子记忆：通过亚基交换与新合成的蛋白质共享其激活状态，以存储多年的记忆。 Ca2+-钙调蛋白依赖性蛋白激酶 II (CaMKII) 被确定为一种酶，可以符合这个描述。例如，CaMKII 在对其功能至关重要的位点发生突变会导致严重的学习障碍和记忆缺陷。 CaMKII 在阈值神经元尖峰频率下被激活，对于长期生存至关重要增强作用（LTP）。理解 LTP 的一个主要障碍是不了解监管如何在最初的高频刺激过程中招募的通路能够在面部保持持续活跃持续的蛋白质周转。我们最近的工作表明 CaMKII 在全酶以激活依赖性方式。重要的是，激酶活性被赋予未激活的由于亚基交换，CaMKII 全酶通过转磷酸化，从而增强蛋白质降解后的激活信号。这个循环可能会无限期地持续下去。我们的工作是旨在进一步研究这种现象，特别是其在 LTP 中的作用。我们的主要研究目标是： 1) 了解 CaMKII 独特生物物理特性的作用（接头长度如何影响激活、频率依赖性和亚基交换），这些因素有助于其成为“记忆”的潜力分子，”和 2) 研究 CaMKII 的特性（例如亚基交换和基因变化）表达），以确定其在 LTP 中的生理作用。这些具有挑战性的目标需要从分子水平（蛋白质结构和调控）到细胞水平获得的信息的综合（哺乳动物细胞培养），最后达到动物水平（转基因小鼠），这将用于未来的研究。完成拟议的工作将使我们能够更好地解决影响神经系统疾病的进展记忆，例如阿尔茨海默氏症、痴呆症和创伤性脑损伤中出现的病症。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional implications of CaMKII alternative splicing.

CaMKII 选择性剪接的功能意义。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Sloutsky, Roman;Stratton, Margaret M
通讯作者：
Stratton, Margaret M

Live-cell FLIM-FRET using a commercially available system.

使用市售系统的活细胞 FLIM-FRET。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Castellani, Colleen M;Torres;Breffke, Jens;White, Adam B;Chambers, James J;Stratton, Margaret M;Maresca, Thomas J
通讯作者：
Maresca, Thomas J

FRET-based sensor for CaMKII activity (FRESCA): A useful tool for assessing CaMKII activity in response to Ca2+ oscillations in live cells.

基于 FRET 的 CaMKII 活性传感器 (FRESCA)：用于评估活细胞中 Ca2+ 振荡响应的 CaMKII 活性的有用工具。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Ardestani, Goli;West, Megan C;Maresca, Thomas J;Fissore, Rafael A;Stratton, Margaret M
通讯作者：
Stratton, Margaret M

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Margaret M Stratton其他文献

A domain-swapped CaMKII conformation facilitates linker-mediated allosteric regulation

结构域交换的 CaMKII 构象促进接头介导的变构调节

DOI：
10.1101/2024.03.24.586494
发表时间：
2024-03-27
期刊：
bioRxiv
影响因子：
0
作者：
Bao V. Nguyen;Can Özden;Kairong Dong;Ana P. Torres;Noelle Dziedzic;Daniel Flaherty;Jian Huang;Saketh Sankura;Nikki Lyn Abromson;D. Tomchick;Jianhan Chen;S. Garman;Margaret M Stratton
通讯作者：
Margaret M Stratton