Modelling the effect of specific inositol 1,4,5-trisphosphate receptor isoforms on cellular Ca2+ signals
Modelling the effect of specific inositol 1,4,5-trisphosphate receptor isoforms on cellular Ca2+ signals
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DOI：
10.1042/bc20050032
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发表时间：
2006-03-01
影响因子：
2.7
通讯作者：
Combettes, L
中科院分区：
文献类型：
--
作者：
Dupont, G;Combettes, L
背景资料。众所周知，胞质Ca 2+的振荡依赖于InsP（3）R（肌醇1，4，5-三磷酸受体）的调节特性。已经鉴定了该通道的三种亚型。它们在Ca 2+和InsP（3）的调节特性方面有所不同。在不同细胞类型中的实验清楚地表明，每种亚型的相对量影响激动剂刺激后Ca 2+变化的时间过程。在本研究中，我们调查是否不同的稳态曲线的开放概率的lnsP（3）Rs作为Ca 2+的函数意味着不同的动力学行为时，这些受体存在于细胞环境中。因此，我们描述了一个特定的现象学模型的三种主要类型的曲线，已报道：（i）经典的钟形曲线，（ii）钟形曲线，移向更高的Ca 2+浓度时，InsP（3）增加，和（iii）一个单调的增加函数的胞浆Ca 2+。我们发现，尽管这些类型的曲线可以归因于Ca 2+和InsP（3）在通道调节方面的微小差异，但它们可以表明细胞Ca 2+控制中受体作用的重要变化。因此，与经典钟形曲线相关的受体似乎是最稳健的Ca 2+振荡器。如果稳态曲线被认为是一个单调递增的函数的胞质Ca 2+，模拟的受体不能维持Ca 2+振荡的情况下，与细胞外介质的Ca 2+交换。当钟形曲线随着InsP（3）水平的增加而向更高的Ca 2+浓度移动时，模型预测受体对密度变化的鲁棒性较低;然而，当改变InsP（3）浓度时，该受体提供了对稳态Ca 2+水平的更精细控制。我们的模型使我们能够对选择性表达或下调InsP（3）R亚型的实验观察结果提出解释，并进行理论预测。
Background information. Oscillations of cytosolic Ca2+ are well-known to rely on the regulatory properties of the InsP(3)R (inositol 1,4,5-trisphosphate receptor). Three isoforms of this channel have been identified. They differ in their regulatory properties by Ca2+ and InsP(3). Experiments in different cell types clearly indicate that the relative amounts of each isoform affect the time course of Ca2+ changes after agonist stimulation. In the present study, we investigate whether different steady-state curves for the open probability of the lnsP(3)Rs as a function of Ca2+ imply different dynamical behaviours when these receptors are present in a cellular environment. We therefore describe by a specific phenomenological model the three main types of curves that have been reported: (i) the classical bell-shaped curve, (ii) the bell-shaped curve that is shifted towards higher Ca2+ concentrations when InsP(3) is increased, and (iii) a monotonous increasing function of cytosolic Ca2+.Results. We show that, although these types of curves can be ascribed to slight differences in the channel regulation by Ca2+ and InsP(3), they can indicate important variations as to the receptor role in cellular Ca2+ control. Thus the receptor associated with the classical bell-shaped curve appears to be the most robust Ca2+ oscillator. If the steady-state curve is supposed to be a monotonous increasing function of cytosolic Ca2+, the modelled receptor cannot sustain Ca2+ oscillations in the absence of Ca2+ exchanges with the extracellular medium. When the bell-shaped curve is shifted towards higher Ca2+ concentrations with increasing InsP(3) levels, the model predicts that the receptor is less robust to changes in density; this receptor, however, provides a finer control of the steady-state level of Ca2+ when varying the InsP(3) concentration.Conclusions. Our model allows us to propose an explanation for the experimental observations about the effect of selectively expressing or down-regulating InsP(3)R isoforms, as well as to make theoretical predictions.