Matolcsi Matt, Giordano Nicholas
Department of Physics, Purdue University, West Lafayette, Indiana.
Department of Physics, Auburn University, Auburn, Alabama.
Biophys J. 2015 Feb 17;108(4):975-985. doi: 10.1016/j.bpj.2014.12.044.
We present a simplified reaction network in a single well-mixed volume that captures the general features of CaMKII dynamics observed during both synaptic input and spine depolarization. Our model can also account for the greater-than-control CaMKII activation observed with added EGTA during depolarization. Calcium input currents are modeled after experimental observations, and existing models of calmodulin and CaMKII autophosphorylation are used. After calibration against CaMKII activation data in the absence of chelators, CaMKII activation dynamics due to synaptic input via n-methyl-d-aspartate receptors are qualitatively accounted for in the presence of the chelators EGTA and BAPTA without additional adjustments to the model. To account for CaMKII activation dynamics during spine depolarization with added EGTA or BAPTA, the model invokes the modulation of CaV2.3 (R-type) voltage-dependent calcium channel (VDCC) currents observed in the presence of EGTA or BAPTA. To our knowledge, this is a novel explanation for the increased CaMKII activation seen in dendritic spines with added EGTA, and suggests that differential modulation of VDCCs by EGTA and BAPTA offers an alternative or complementary explanation for other experimental results in which addition of EGTA or BAPTA produces different effects. Our results also show that a simplified reaction network in a single, well-mixed compartment is sufficient to account for the general features of observed CaMKII dynamics.
我们提出了一个简化的反应网络，它存在于一个单一的充分混合的体积中，能够捕捉在突触输入和树突棘去极化过程中观察到的CaMKII动力学的一般特征。我们的模型还可以解释在去极化过程中添加EGTA时观察到的比对照更高的CaMKII激活现象。钙输入电流是根据实验观察结果进行建模的，并使用了现有的钙调蛋白和CaMKII自磷酸化模型。在针对无螯合剂时的CaMKII激活数据进行校准后，在存在螯合剂EGTA和BAPTA的情况下，无需对模型进行额外调整，就能定性地解释通过N-甲基-D-天冬氨酸受体的突触输入所导致的CaMKII激活动力学。为了解释在添加EGTA或BAPTA的情况下树突棘去极化过程中的CaMKII激活动力学，该模型引入了在存在EGTA或BAPTA时观察到的CaV2.3（R型）电压依赖性钙通道（VDCC）电流的调制。据我们所知，这是对添加EGTA时在树突棘中观察到的CaMKII激活增加的一种新解释，并表明EGTA和BAPTA对VDCC的差异调制为其他实验结果提供了一种替代或补充解释，在这些实验中添加EGTA或BAPTA会产生不同的效果。我们的结果还表明，在一个单一的、充分混合的隔室中的简化反应网络足以解释观察到的CaMKII动力学的一般特征。
