Competitive Tuning Among Ca2+/Calmodulin-Dependent Proteins: Analysis of In Silico Model Robustness and Parameter Variability
Competitive Tuning Among Ca2+/Calmodulin-Dependent Proteins: Analysis of In Silico Model Robustness and Parameter Variability
复制标题
Ca2/钙调蛋白依赖性蛋白质之间的竞争性调节：计算机模型稳健性和参数变异性分析
DOI：
10.1007/s12195-018-0549-4
复制
发表时间：
2018
影响因子：
2.8
通讯作者：
Kinzer-Ursem, Tamara L.
中科院分区：
文献类型：
--
作者：
Pharris, Matthew C.;Patel, Neal M.;Kinzer-Ursem, Tamara L.
钙/钙调素依赖（Ca 2 +/CaM-dependent）的蛋白质信号转导调节在许多生理学背景中一直被认为是重要的。在几乎所有的真核细胞中发现，Ca 2 +/CaM依赖性信号传导参与肌肉发育、免疫应答、心肌细胞功能和神经元连接的调节。在兴奋性神经元中，当钙离子（Ca 2+）流过NMDA受体并结合Ca 2+传感器钙调蛋白（CaM）时，发生突触连接强度的动态变化，称为突触可塑性。Ca 2 +/CaM反过来调节肌动蛋白聚合、受体运输和转录因子激活中的下游蛋白质信号传导。下游Ca 2 +/CaM依赖性结合蛋白（CBP）的激活是Ca 2+通量频率的函数，因此每个CBP优先“调谐”到不同的Ca 2+输入信号。我们最近报道，竞争之间的CBPs钙调素结合是单独足以recreatein silicothe vedin vivoffrequency-dependencyof几个CBPs。然而，CBP激活可能强烈地依赖于构成竞争池的蛋白质的身份和浓度;在正常和疾病状态下CBPs的调节中具有重要意义。MethodsHere，我们扩展了我们以前的CBPs之间竞争的确定性模型，包括磷酸二酯酶，AMPAR受体，这在突触可塑性中是重要的，CBPs的酶功能：cAMP调节、激酶活性和磷酸酶活性。经过严格的参数化和验证的全球敏感性分析，使用拉丁超立方体采样（LHS）和部分秩相关系数（PRCC），我们探讨如何扰动竞争池的CBP影响下游信号事件。特别是，我们假设，虽然扰动可能会减少激活的一个CBP，增加激活的一个单独的，但酶相关的CBP可以弥补这种损失，提供一个稳态的effect.Results和ConclusionsFirst我们比较两个模型的动态模型输出：一个两态模型的Ca 2 +/CaM结合和四态模型的Ca 2 +/CaM结合。我们发现，一个四态模型的Ca 2 +/CaM结合最好的捕获的动态性质的CaM和CBPs的快速响应的Ca 2+通量在系统中。利用全局灵敏度分析，我们发现模型输出对参数变化具有鲁棒性。事实上，尽管CaM缓冲神经颗粒蛋白（Ng）表达的变化可能导致Ca 2 +/CaM依赖性激酶II（CaMKII）活化的减少，但总体AMPA受体磷酸化被保留;表面上是通过腺苷酸环化酶8（AC 8）介导的蛋白激酶A（PKA）活化的伴随增加。事实上，通过CaMKII和PKA的AMPAR受体的磷酸化在宽范围的Ng浓度下是稳健的，尽管在接近零的低Ng水平下观察到AMPAR磷酸化的增加。我们的研究结果可以解释最近在神经颗粒蛋白基因敲除小鼠中的反直觉结果，并提供进一步的证据表明，竞争性调谐是突触可塑性的一个重要机制。这些结果可以很容易地转化为其他细胞类型中的其他Ca 2 +/CaM依赖性信号传导系统，并可用于建议有针对性的实验研究，以解释反直觉或意外的下游信号传导结果。
IntroductionCalcium/calmodulin-dependent (Ca2+/CaM-dependent) regulation of protein signaling has long been recognized for its importance in a number of physiological contexts. Found in almost all eukaryotic cells, Ca2+/CaM-dependent signaling participates in muscle development, immune responses, cardiac myocyte function and regulation of neuronal connectivity. In excitatory neurons, dynamic changes in the strength of synaptic connections, known as synaptic plasticity, occur when calcium ions (Ca2+) flux through NMDA receptors and bind the Ca2+-sensor calmodulin (CaM). Ca2+/CaM, in turn, regulates downstream protein signaling in actin polymerization, receptor trafficking, and transcription factor activation. The activation of downstream Ca2+/CaM-dependent binding proteins (CBPs) is a function of the frequency of Ca2+flux, such that each CBP is preferentially “tuned” to different Ca2+input signals. We have recently reported that competition among CBPs for CaM binding is alone sufficient to recreatein silicothe observedin vivofrequency-dependence of several CBPs. However, CBP activation may strongly depend on the identity and concentration of proteins that constitute the competitive pool; with important implications in the regulation of CBPs in both normal and disease states.MethodsHere, we extend our previous deterministic model of competition among CBPs to include phosphodiesterases, AMPAR receptors that are important in synaptic plasticity, and enzymatic function of CBPs: cAMP regulation, kinase activity, and phosphatase activity. After rigorous parameterization and validation by global sensitivity analysis using Latin Hypercube Sampling (LHS) and Partial Rank Correlation Coefficients (PRCC), we explore how perturbing the competitive pool of CBPs influences downstream signaling events. In particular, we hypothesize that although perturbations may decrease activation of one CBP, increased activation of a separate, but enzymatically-related CBP could compensate for this loss, providing a homeostatic effect.Results and ConclusionsFirst we compare dynamic model output of two models: a two-state model of Ca2+/CaM binding and a four-state model of Ca2+/CaM binding. We find that a four-state model of Ca2+/CaM binding best captures the dynamic nature of the rapid response of CaM and CBPs to Ca2+flux in the system. Using global sensitivity analysis, we find that model output is robust to parameter variability. Indeed, although variations in the expression of the CaM buffer neurogranin (Ng) may cause a decrease in Ca2+/CaM-dependent kinase II (CaMKII) activation, overall AMPA receptor phosphorylation is preserved; ostensibly by a concomitant increase in adenylyl cyclase 8 (AC8)-mediated activation of protein kinase A (PKA). Indeed phosphorylation of AMPAR receptors by CaMKII and PKA is robust across a wide range of Ng concentrations, though increases in AMPAR phosphorylation is seen at low Ng levels approaching zero. Our results may explain recent counter-intuitive results in neurogranin knockout mice and provide further evidence that competitive tuning is an important mechanism in synaptic plasticity. These results may be readily translated to other Ca2+/CaM-dependent signaling systems in other cell types and can be used to suggest targeted experimental investigation to explain counter-intuitive or unexpected downstream signaling outcomes.
登录
查看更多内容
影响因子：
4.3
作者：
Romano DR;Pharris MC;Patel NM;Kinzer-Ursem TL
通讯作者：
Kinzer-Ursem TL
DOI：
10.1073/pnas.87.2.682
发表时间：
1990-01-01
影响因子：
11.1
作者：
BREDT, DS;SNYDER, SH
通讯作者：
SNYDER, SH
大鼠脑腺苷酸环化酶的溶解、稳定和部分纯化。
影响因子：
2.9
作者：
N. I. Swislocki;J. Tierney
通讯作者：
J. Tierney
Ca2/钙调蛋白激活蛋白的竞争性调节为突触可塑性中的 AMPA 受体磷酸化提供了补偿机制
DOI：
--
发表时间：
2018
期刊：
影响因子：
--
作者：
Matthew C. Pharris;Tamara L. Kinzer
通讯作者：
Tamara L. Kinzer
大鼠脑中 Ca2+/钙调蛋白敏感和 Ca2+ 不敏感腺苷酸环化酶的离散表达
影响因子：
2.3
作者：
N. Mons;M. Yoshimura;D. Cooper
通讯作者：
D. Cooper