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首页> 外文期刊>PLoS Computational Biology >A Dynamic Model of Interactions of Ca 2+ , Calmodulin, and Catalytic Subunits of Ca 2+ /Calmodulin-Dependent Protein Kinase II
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A Dynamic Model of Interactions of Ca 2+ , Calmodulin, and Catalytic Subunits of Ca 2+ /Calmodulin-Dependent Protein Kinase II

机译：Ca 2+，钙调蛋白和Ca 2+ /钙调蛋白依赖性蛋白激酶II的催化亚基相互作用的动力学模型

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During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-d-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+ influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+ with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning.
机译：在获得记忆的过程中，Ca2 +通过活化的N-甲基-d-天冬氨酸型谷氨酸受体的孔流入突触后脊柱，触发了改变兴奋性突触强度的过程。在活动的最初几秒钟内，Ca2 +内流的模式在依赖于Ca2 +的信号网络中得到解释，从而最终增强或降低了突触强度。许多控制突触可塑性的关键信号转导酶，包括Ca2 + /钙调蛋白依赖性蛋白激酶II（CaMKII），均受钙调蛋白调节，钙调蛋白是一种小蛋白，最多可结合4个Ca2 +离子。作为阐明Ca2 +信号网络如何决定增强还是抑制的第一步，我们创建了Ca2 +，钙调蛋白和CaMKII相互作用的动力学模型，该模型代表了我们对类似于这些条件的相互作用的动力学的最佳理解。在突触后脊柱中。我们从文献数据或我们自己的测量中约束模型的参数，然后预测CaMKII在各种条件下的激活和自磷酸化的时间过程。模拟显示，结合钙离子少于4个的钙调蛋白物种在生理机制中对CaMKII的激活起着重要作用，支持以下观点：脊柱中Ca2 +信号的处理涉及靶酶之间的竞争，以结合CaM +中的不饱和物种。 Ca2 +浓度快速波动的环境。确实，我们表明激活对Ca2 +瞬变频率的依赖性是由波动的Ca2 +与钙调蛋白/ CaMKII复合物相互作用的动力学引起的。我们使用参数敏感性分析来确定哪些参数将最有利于更仔细地进行测量以提高预测的准确性。该模型提供了一个定量的基础，从该基础可以构建学习过程中突触后信号转导的更复杂的动态模型。

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