Institut für Physik, Humboldt-Universität zu Berlin, Berlin, Germany.
PLoS Comput Biol. 2012 May;8(5):e1002485. doi: 10.1371/journal.pcbi.1002485. Epub 2012 May 31.
In many cell types, release of calcium ions is controlled by inositol 1,4,5-trisphosphate (IP₃) receptor channels. Elevations in Ca²⁺ concentration after intracellular release through IP₃ receptors (IP₃R) can either propagate in the form of waves spreading through the entire cell or produce spatially localized puffs. The appearance of waves and puffs is thought to implicate random initial openings of one or a few channels and subsequent activation of neighboring channels because of an "autocatalytic" feedback. It is much less clear, however, what determines the further time course of release, particularly since the lifetime is very different for waves (several seconds) and puffs (around 100 ms). Here we study the lifetime of Ca²⁺ signals and their dependence on residual Ca²⁺ microdomains. Our general idea is that Ca²⁺ microdomains are dynamical and mediate the effect of other physiological processes. Specifically, we focus on the mechanism by which Ca²⁺ binding proteins (buffers) alter the lifetime of Ca²⁺ signals. We use stochastic simulations of channel gating coupled to a coarse-grained description for the Ca²⁺ concentration. To describe the Ca²⁺ concentration in a phenomenological way, we here introduce a differential equation, which reflects the buffer characteristics by a few effective parameters. This non-stationary model for microdomains gives deep insight into the dynamical differences between puffs and waves. It provides a novel explanation for the different lifetimes of puffs and waves and suggests that puffs are terminated by Ca²⁺ inhibition while IP₃ unbinding is responsible for termination of waves. Thus our analysis hints at an additional role of IP3 and shows how cells can make use of the full complexity in IP₃R gating behavior to achieve different signals.
在许多细胞类型中，钙离子的释放受肌醇 1,4,5-三磷酸（IP₃）受体通道控制。通过 IP₃ 受体（IP₃R）在细胞内释放后，钙离子浓度的升高可以以波的形式在整个细胞中传播，也可以产生空间局部的爆发。波和爆发的出现被认为涉及一个或几个通道的随机初始开放，以及由于“自催化”反馈而激活相邻通道。然而，释放的进一步时间过程是由什么决定的，这一点远不清楚，特别是因为波的寿命（几秒钟）和爆发（约 100 毫秒）非常不同。在这里，我们研究钙离子信号的寿命及其对残留钙离子微区的依赖性。我们的总体思路是，钙离子微区是动态的，并介导其他生理过程的影响。具体来说，我们专注于钙离子结合蛋白（缓冲剂）改变钙离子信号寿命的机制。我们使用通道门控的随机模拟，结合钙离子浓度的粗粒化描述。为了以一种现象学的方式描述钙离子浓度，我们在这里引入了一个微分方程，通过几个有效参数来反映缓冲剂的特性。这种用于微区的非稳态模型深入了解了爆发和波之间的动力学差异。它为爆发和波的不同寿命提供了新颖的解释，并表明爆发是由钙离子抑制终止的，而 IP₃ 的解联是波终止的原因。因此，我们的分析暗示了 IP3 的额外作用，并展示了细胞如何利用 IP3R 门控行为的全部复杂性来实现不同的信号。
