Biochemical principles underlying the stable maintenance of LTP by the CaMKII/NMDAR complex.
Biochemical principles underlying the stable maintenance of LTP by the CaMKII/NMDAR complex.
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DOI：
10.1016/j.brainres.2014.12.010
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发表时间：
2015-09-24
期刊：
影响因子：
2.9
通讯作者：
Raghavachari, Sriclhar
中科院分区：
文献类型：
--
作者：
Lisman, John;Raghavachari, Sriclhar
记忆涉及通过类似LTP的过程在突触存储信息。这种信息存储是突触特有的，即使所有突触蛋白发生翻转，这种存储也可以持续数年。因此，必须有特殊的原则来支撑LTP的稳定性。最近的实验结果表明，LTP是由CaMKII与NMDAR的络合物维持的。在这里，我们考虑CaMKII/NMDAR分子开关的细节，目的是了解突触稳定信息存储的生化原理。对各种实验结果的考虑表明，这涉及到多个原则。一个开关要求是防止从OFF状态到ON状态的自发转换。CaMKII被钙离子自动磷酸化的高度合作性(Hill系数为8)以及CaMKII/NMDAR复合体的形成需要从肌动蛋白中释放CaMKII的事实是稳定关闭状态的机制。ON状态的稳定性关键依赖于亚基间的自磷酸化，这一过程可以修复由于磷酸酶活性而导致的pT286的任何丢失。亚基间的自动磷酸化也是解释为什么蛋白质周转不会影响状态稳定性的重要原因。最近的证据表明，营业额是通过亚单位交换发生的。因此，如果新插入的未磷酸化的亚基被邻近的亚基自动磷酸化，则可以实现稳定性。基于最近的其他工作，我们提出了一种新的机制，即通过保护pT286不受磷酸酶的影响来增强ON状态的稳定性。我们假设NMNDAR与CaMKII的结合迫使pT286进入邻近亚基的催化位置，从而保护pT286免受磷酸酶的影响。最后一条原则涉及结构性改革的作用。CaMKII与NMDAR的结合可能作为一个标签，组织进一步的蛋白质结合，产生晚期LTP背后的突触扩大。我们认为，这些结构变化不仅增强了传递，而且增强了CaMKII/NMDAR复合体的稳定性。总而言之，这些原理为理解单个突触如何产生稳定的信息存储提供了一个机械框架。
Memory involves the storage of information at synapses by an LTP-like process. This information storage is synapse specific and can endure for years despite the turnover of all synaptic proteins. There must, therefore, be special principles that underlie the stability of LTP. Recent experimental results suggest that LTP is maintained by the complex of CaMKII with the NMDAR. Here we consider the specifics of the CaMKII/NMDAR molecular switch, with the goal of understanding the biochemical principles that underlie stable information storage by synapses. Consideration of a variety of experimental results suggests that multiple principles are involved. One switch requirement is to prevent spontaneous transitions from the off to the on state. The highly cooperative nature of CaMKII autophosphorylation by Ca2+ (Hill coefficient of 8) and the fact that formation of the CaMKII/NMDAR complex requires release of CaMKII from actin are mechanisms that stabilize the off state. The stability of the on state depends critically on intersubunit autophosphorylation, a process that restores any loss of pT286 due to phosphatase activity. Intersubunit autophosphorylation is also important in explaining why on state stability is not compromised by protein turnover. Recent evidence suggests that turnover occurs by subunit exchange. Thus, stability could be achieved if a newly inserted unphosphorylated subunit was autophosphorylated by a neighboring subunit. Based on other recent work, we posit a novel mechanism that enhances the stability of the on state by protection of pT286 from phosphatases. We posit that the binding of the NMNDAR to CaMKII forces pT286 into the catalytic site of a neighboring subunit, thereby protecting pT286 from phosphatases. A final principle concerns the role of structural changes. The binding of CaMKII to the NMDAR may act as a tag to organize the binding of further proteins that produce the synapse enlargement that underlies late LTP. We argue that these structural changes not only enhance transmission, but also enhance the stability of the CaMKII/NMDAR complex. Together, these principles provide a mechanistic framework for understanding how individual synapses produce stable information storage.
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