Hashambhoy Yasmin L, Winslow Raimond L, Greenstein Joseph L
Institute for Computational Medicine, Center for Cardiovascular Bioinformatics and Modeling, and the Whitaker Biomedical Engineering Institute, the Johns Hopkins University, Baltimore, Maryland, USA.
Biophys J. 2009 Mar 4;96(5):1770-85. doi: 10.1016/j.bpj.2008.11.055.
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays an important role in L-type Ca(2+) channel (LCC) facilitation: the Ca(2+)-dependent augmentation of Ca(2+) current (I(CaL)) exhibited during rapid repeated depolarization. Multiple mechanisms may underlie facilitation, including an increased rate of recovery from Ca(2+)-dependent inactivation and a shift in modal gating distribution from mode 1, the dominant mode of LCC gating, to mode 2, a mode in which openings are prolonged. We hypothesized that the primary mechanism underlying facilitation is the shift in modal gating distribution resulting from CaMKII-mediated LCC phosphorylation. We developed a stochastic model describing the dynamic interactions among CaMKII, LCCs, and phosphatases as a function of dyadic Ca(2+) and calmodulin levels, and we incorporated it into an integrative model of the canine ventricular myocyte. The model reproduces behaviors at physiologic protein levels and allows for dynamic transition between modes, depending on the LCC phosphorylation state. Simulations showed that a CaMKII-dependent shift in LCC distribution toward mode 2 accounted for the I(CaL) positive staircase. Moreover, simulations demonstrated that experimentally observed changes in LCC inactivation and recovery kinetics may arise from modal gating shifts, rather than from changes in intrinsic inactivation properties. The model therefore serves as a powerful tool for interpreting I(CaL) experiments.
钙/钙调蛋白依赖性蛋白激酶II（CaMKII）在L型钙通道（LCC）易化过程中发挥重要作用：即快速重复去极化期间所表现出的Ca²⁺电流（I(CaL)）的Ca²⁺依赖性增强。易化过程可能有多种机制，包括从Ca²⁺依赖性失活的恢复速率增加以及门控模式分布从模式1（LCC门控的主导模式）向模式2（一种开放时间延长的模式）的转变。我们推测易化的主要机制是CaMKII介导的LCC磷酸化导致的门控模式分布转变。我们开发了一个随机模型，该模型描述了CaMKII、LCC和磷酸酶之间作为二元Ca²⁺和钙调蛋白水平函数的动态相互作用，并将其纳入犬心室肌细胞的整合模型中。该模型在生理蛋白水平上再现了相关行为，并允许根据LCC磷酸化状态在模式之间进行动态转换。模拟结果表明，LCC分布向模式2的CaMKII依赖性转变解释了I(CaL)的正向阶梯现象。此外,模拟结果表明，实验观察到的LCC失活和恢复动力学变化可能源于门控模式的转变，而非内在失活特性的改变。因此，该模型是解释I(CaL)实验的有力工具。
