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首页> 外文期刊>PLoS Computational Biology >Analyzing and Quantifying the Gain-of-Function Enhancement of IP3 Receptor Gating by Familial Alzheimer’s Disease-Causing Mutants in Presenilins
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Analyzing and Quantifying the Gain-of-Function Enhancement of IP3 Receptor Gating by Familial Alzheimer’s Disease-Causing Mutants in Presenilins

机译：分析和量化Presenilins在Presenilins致病突变体的IP3受体伴随的功能增益

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Familial Alzheimer’s disease (FAD)-causing mutant presenilins (PS) interact with inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) Ca2+ release channels resulting in enhanced IP3R channel gating in an amyloid beta (Aβ) production-independent manner. This gain-of-function enhancement of IP3R activity is considered to be the main reason behind the upregulation of intracellular Ca2+ signaling in the presence of optimal and suboptimal stimuli and spontaneous Ca2+ signals observed in cells expressing mutant PS. In this paper, we employed computational modeling of single IP3R channel activity records obtained under optimal Ca2+ and multiple IP3 concentrations to gain deeper insights into the enhancement of IP3R function. We found that in addition to the high occupancy of the high-activity (H) mode and the low occupancy of the low-activity (L) mode, IP3R in FAD-causing mutant PS-expressing cells exhibits significantly longer mean life-time for the H mode and shorter life-time for the L mode, leading to shorter mean close-time and hence high open probability of the channel in comparison to IP3R in cells expressing wild-type PS. The model is then used to extrapolate the behavior of the channel to a wide range of IP3 and Ca2+ concentrations and quantify the sensitivity of IP3R to its two ligands. We show that the gain-of-function enhancement is sensitive to both IP3 and Ca2+ and that very small amount of IP3 is required to stimulate IP3R channels in the presence of FAD-causing mutant PS to the same level of activity as channels in control cells stimulated by significantly higher IP3 concentrations. We further demonstrate with simulations that the relatively longer time spent by IP3R in the H mode leads to the observed higher frequency of local Ca2+ signals, which can account for the more frequent global Ca2+ signals observed, while the enhanced activity of the channel at extremely low ligand concentrations will lead to spontaneous Ca2+ signals in cells expressing FAD-causing mutant PS.
机译：家族性阿尔茨海默病（FAD） - 用于突变突变素（PS）与肌醇1,4,5-三磷酸（IP3）受体（IP3R）CA2 +释放通道相互作用，导致淀粉样蛋白β（Aβ）的淀粉样蛋白β（Aβ）的增强的IP3R通道相互作用。这种功能性增强IP3R活性被认为是在表达突变体PS中的细胞中观察到的最佳和次优刺激和自发CA2 +信号的存在下的细胞内Ca2 +信号传导背后的主要原因。在本文中，我们采用了在最佳CA2 +和多个IP3浓度下获得的单个IP3R信道活动记录的计算建模，以增强IP3R功能增强的更深层次的见解。我们发现除了高活度（H）模式的高占用和低活性（L）模式的低占用之外，IP3R在FAD引起的突变体PS表达细胞中表现出明显更长的平均寿命时间H模式和L模式的较短寿命，导致较短的平均特写，因此与表示野生型PS的电池中的IP3R相比，通道的高开放概率。然后使用该模型将通道的行为推断到宽范围的IP3和CA2 +浓度，并量化IP3R对其两个配体的敏感性。我们表明，函数增益增强对IP3和CA2 +敏感，并且需要非常少量的IP3来刺激在存在FAD导致突变场PS到与控制单元中相同的活动水平相同的活动水平的IP3R通道通过显着较高的IP3浓度刺激。我们进一步说明了模拟，即IP3R在H模式中花费的时间相对较长的时间导致观察到的本地CA2 +信号的较高频率，这可以考虑观察到的更频繁的全局CA2 +信号，而频道的增强活动极低配体浓度将导致在表达FAD导致突变体PS的细胞中产生自发的CA2 +信号。

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