Interactions between calmodulin and neurogranin govern the dynamics of CaMKII as a leaky integrator
Interactions between calmodulin and neurogranin govern the dynamics of CaMKII as a leaky integrator
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DOI：
10.1371/journal.pcbi.1008015
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发表时间：
2019-10
影响因子：
4.3
通讯作者：
Mariam Ordyan;Tomas M. Bartol;M. Kennedy;P. Rangamani;T. Sejnowski
中科院分区：
文献类型：
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作者：
Mariam Ordyan;Tomas M. Bartol;M. Kennedy;P. Rangamani;T. Sejnowski
钙调素依赖性激酶II （CaMKII）在学习和记忆以及长期增强（LTP）中发挥着重要作用。最近有人提出，它可能与突触信号的时间平均有关，这可以导致存储在单个突触中的信息的高精度。然而，支架分子神经颗粒蛋白（Ng）在CaMKII动力学中的作用尚不完全清楚。在这项工作中，我们采用基于规则的建模方法，通过蒙特卡罗方法研究Ca2+信号对突触后密度（PSD）中CaMKII磷酸化动力学的影响。在EPSP和反向传播动作电位期间，由于NMDA受体和电压依赖性钙通道的开放，在突触棘中观察到钙浪涌。我们研究了CaMKII单体和十二聚体全酶磷酸化动力学的差异。当支架分子Ng以显著浓度存在时，会限制游离钙调素（CaM）的可用性，这种蛋白质在钙存在时激活CaMKII。我们发现它在高钙浓度激增后对CaMKII磷酸化起重要的调节作用。我们发现这种影响与CaM浓度的非直观依赖关系，这是由于CaM对CaMKII的不同亲和力取决于与前者结合的钙离子的数量。先前已经表明，在缺乏磷酸酶的情况下，CaMKII单体通过自磷酸化在特定频率的Ca2+信号上整合（Pepke等人，Plos Comp. Bio）。, 2010)。我们还研究了多个钙峰对CaMKII全酶自磷酸化的影响，并表明在磷酸酶存在的情况下，CaMKII表现为钙信号的漏积者，这是最近在体内观察到的结果。我们的模型预测，该泄漏积分器的参数通过Ng、CaM、CaMKII和PP1的相互作用被精细地调整。这可能是一种精确控制突触对钙信号敏感性的机制。
Calmodulin-dependent kinase II (CaMKII) has long been known to play an important role in learning and memory as well as long term potentiation (LTP). More recently it has been suggested that it might be involved in the time averaging of synaptic signals, which can then lead to the high precision of information stored at a single synapse. However, the role of the scaffolding molecule, neurogranin (Ng), in governing the dynamics of CaMKII is not yet fully understood. In this work, we adopt a rule-based modeling approach through the Monte Carlo method to study the effect of Ca2+ signals on the dynamics of CaMKII phosphorylation in the postsynaptic density (PSD). Calcium surges are observed in synaptic spines during an EPSP and back-propagating action potential due to the opening of NMDA receptors and voltage dependent calcium channels. We study the differences between the dynamics of phosphorylation of CaMKII monomers and dodecameric holoenzymes. The scaffolding molecule Ng, when present in significant concentration, limits the availability of free calmodulin (CaM), the protein which activates CaMKII in the presence of calcium. We show that it plays an important modulatory role in CaMKII phosphorylation following a surge of high calcium concentration. We find a non-intuitive dependence of this effect on CaM concentration that results from the different affinities of CaM for CaMKII depending on the number of calcium ions bound to the former. It has been shown previously that in the absence of phosphatase CaMKII monomers integrate over Ca2+ signals of certain frequencies through autophosphorylation (Pepke et al, Plos Comp. Bio., 2010). We also study the effect of multiple calcium spikes on CaMKII holoenzyme autophosphorylation, and show that in the presence of phosphatase CaMKII behaves as a leaky integrator of calcium signals, a result that has been recently observed in vivo. Our models predict that the parameters of this leaky integrator are finely tuned through the interactions of Ng, CaM, CaMKII, and PP1. This is a possible mechanism to precisely control the sensitivity of synapses to calcium signals.