Modulatory effect of calmodulin-dependent kinase II (CaMKII) on sarcoplasmic reticulum Ca2+ handling and interval-force relations:: a modelling study
Modulatory effect of calmodulin-dependent kinase II (CaMKII) on sarcoplasmic reticulum Ca2+ handling and interval-force relations:: a modelling study
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DOI：
10.1098/rsta.2006.1758
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发表时间：
2006-05-15
期刊：
影响因子：
5
通讯作者：
Noble, D
中科院分区：
文献类型：
--
作者：
Iribe, G;Kohl, P;Noble, D
我们假设Ca2+/钙调素依赖性激酶II （CaMKII）的缓慢失活及其对肌浆网（SR） Ca2+处理的调节作用对于各种间隔力（I-F）关系，特别是在收缩后增强衰减期间瞬态交替中的节拍间隔依赖性是重要的。我们通过将概念性CaMKII动力学模型纳入SR Ca2+处理模型，开发了单个心肌细胞的数学模型，以整合各种I-F关系，包括替代关系。我们的模型集成了I-F关系，如节拍间隔相关的抽搐力持续时间、恢复和增强、正阶梯现象和交替。我们发现CaMKII或多或少地影响了所有的I-F关系，它是我们模型中各种I-F关系整合的关键因素。在该模型中，由于钙离子通过ryanodine受体的释放性的SR负载依赖性变化，在SR Ca2+负载和释放之间存在陡峭的关系。温度间隔依赖性CaMKII活性，由于其动力学性质和Ca2+释放对sr - Ca2+负荷依赖性的放大效应，复制了交替植物的温度间隔依赖性，实验观察到。此外，我们的模型能够再现各种干预措施对替代品的影响，例如减缓或加速Ca2+释放和/或摄取。我们得出的结论是，在CaMKII模型中，一个缓慢的时间依赖性因素对I-F关系的整合很重要，包括替代，我们的模型为进一步分析综合Ca2+处理在心肌I-F关系中的作用提供了一个有用的工具。
We hypothesize that slow inactivation of Ca2+/calmodulin-dependent kinase II (CaMKII) and its modulatory effect on sarcoplasmic reticulum (SR) Ca2+ handling are important for various interval-force (I-F) relations, in particular for the beat interval dependency in transient alternans during the decay of post-extrasystolic potentiation. We have developed a mathematical model of a single cardiomyocyte to integrate various I-F relations, including alternans, by incorporating a conceptual CaMKII kinetics model into the SR Ca2+ handling model. Our model integrates I-F relations, such as the beat interval-dependent twitch force duration, restitution and potentiation, positive staircase phenomenon and alternans. We found that CaMKII affects more or less all I-F relations, and it is a key factor for integration of the various I-F relations in our model. Alternans arises, in the model, out of a steep relation between SR Ca2+ load and release, owing to SR, load-dependent changes in the releasability of Ca2+ via the ryanodine receptor. Beat interval-dependent CaMKII activity, owing to its kinetic properties and amplifying effect on SR. Ca2+ load dependency of Ca2+ release, replicated the beat interval dependency of alternans, as observed experimentally. Additionally, our model enabled reproduction of the effects of various interventions on alternans, such as the slowing or accelerating of Ca2+ release and/or uptake. We conclude that a slow time-dependent factor, represented in the model by CaMKII, is important for the integration of I-F relations, including alternans, and that our model offers a useful tool for further analysis of the roles of integrative Ca2+ handling in myocardial I-F relation.