Yano Kojiro, Petersen Ole H, Tepikin Alexei V
The Physiological Laboratory, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
Biochem J. 2004 Oct 15;383(Pt 2):353-60. doi: 10.1042/BJ20040629.
The effects of ER (endoplasmic reticulum) Ca2+ on cytosolic Ca2+ oscillations in pancreatic acinar cells were investigated using mathematical models of the Ca2+ oscillations. We first examined the mathematical model of SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) to reproduce the highly co-operative inhibitory effect of Ca2+ in the ER lumen on ER Ca2+ uptake in the acinar cells. The model predicts that luminal Ca2+ would most probably inhibit the conversion of the conformation state with luminal Ca2+-binding sites (E2) into the conformation state with cytoplasmic Ca2+-binding sites (E1). The SERCA model derived from this prediction showed dose-response relationships to cytosolic and luminal Ca2+ concentrations that were consistent with the experimental data from the acinar cells. According to a mathematical model of cytosolic Ca2+ oscillations based on the modified SERCA model, a small decrease in the concentration of endoplasmic reticulum Ca2+ (approx. 20% of the total) was sufficient to abolish the oscillations. When a single type of IP3R (IP3 receptor) was included in the model, store depletion decreased the spike frequency. However, the frequency became less sensitive to store depletion when we added another type of IP3R with higher sensitivity to the concentration of free Ca2+ in the cytosol. Bifurcation analysis of the mathematical model showed that the loss of Ca2+ from the ER lumen decreased the sensitivity of cytosolic Ca2+ oscillations to IP3 [Ins(1,4,5)P3]. The addition of a high-affinity IP3R did not alter this property, but significantly decreased the sensitivity of the spike frequency to IP3. Our mathematical model demonstrates how luminal Ca2+, through its effect on Ca2+ uptake, can control cytosolic Ca2+ oscillations.
利用钙离子振荡的数学模型，研究了内质网（ER）钙离子对胰腺腺泡细胞胞质钙离子振荡的影响。我们首先检验了肌浆网/内质网钙离子-ATP酶（SERCA）的数学模型，以重现内质网腔中钙离子对腺泡细胞内质网钙离子摄取的高度协同抑制作用。该模型预测，腔内钙离子很可能会抑制具有腔内钙离子结合位点（E2）的构象状态向具有细胞质钙离子结合位点（E1）的构象状态的转变。基于这一预测得出的SERCA模型显示了与胞质和内质网腔钙离子浓度的剂量反应关系，这与腺泡细胞的实验数据一致。根据基于改良SERCA模型的胞质钙离子振荡数学模型，内质网钙离子浓度的小幅降低（约占总量的20%）足以消除振荡。当模型中包含单一类型的三磷酸肌醇受体（IP3R）时，储存耗竭会降低尖峰频率。然而，当我们添加另一种对胞质中游离钙离子浓度更敏感的IP3R时，频率对储存耗竭的敏感性降低。数学模型的分岔分析表明，内质网腔中钙离子的流失降低了胞质钙离子振荡对三磷酸肌醇[Ins(1,4,5)P3]的敏感性。添加高亲和力的IP3R并没有改变这一特性，但显著降低了尖峰频率对三磷酸肌醇的敏感性。我们的数学模型展示了腔内钙离子如何通过其对钙离子摄取的影响来控制胞质钙离子振荡。
