Edwards Aurélie, Pallone Thomas L
Department of Chemical and Biological Engineering, Tufts University, 4 Colby St., Medford, MA 02155, USA.
Am J Physiol Renal Physiol. 2007 Nov;293(5):F1518-32. doi: 10.1152/ajprenal.00251.2007. Epub 2007 Aug 1.
Ouabain-like factors modulate intracellular Ca2+ concentrations and Ca2+ stores. Recently, a role for Na+-K+-ATPase Na+ transport inhibition as a pivotal event in ouabain signaling was questioned (Kaunitz JD. Am J Physiol Renal Physiol 290: F995-F996, 2006). In the present study, we used a mathematical model of Ca2+ trafficking in cytoplasm and subplasmalemmal microdomains to simulate the pathways through which ouabain can affect Ca2+ signaling: inhibition of active transport by Na+-K+-ATPase alpha1- and alpha2-isoforms, activation of inositol trisphosphate (IP3) production, and increased IP3 receptor (IP3R) conductance. A fundamental prediction is that Na+-K+-ATPase inhibition favors sarcoplasmic reticulum Ca2+ store loading, whereas Src-mediated increases in IP3 production and IP3R sensitization favor store depletion. The model predicts that alpha2-isoform inhibition generates a peak-and-plateau pattern of cytosolic Ca2+ concentration (Ca2+) elevation, whereas alpha1-isoform inhibition yields a monophasic rise. The effects of ouabain-mediated increases in IP3 production or IP3R conductance on Ca2+ depend on their relative distributions between cellular microdomains and the bulk cytoplasm. Simulations suggest that the intracellular localization of IP3 production is a pivotal determinant of the changes in compartmental Ca2+ concentrations that can be induced by ouabain. As a consequence of sequestration of the ouabain-sensitive alpha2-isoform into microdomains, inhibition of the alpha2-isoform in rodents is not predicted to significantly affect cytosolic Na+ concentration. Model simulations support the hypothesis that ouabain can enhance agonist-evoked Ca2+ transients when its predominant effect is to inhibit alpha2-isoform Na+ transport and, thereby, increase Ca2+ loading into sarcoplasmic reticulum stores.
哇巴因样因子可调节细胞内钙离子浓度及钙离子储存。最近，有人对钠钾ATP酶钠转运抑制作为哇巴因信号传导中的关键事件这一作用提出了质疑（考尼茨·J·D.《美国生理学杂志·肾脏生理学》290:F995 - F996,2006）。在本研究中，我们使用了细胞质和质膜下微区中钙离子转运的数学模型，以模拟哇巴因影响钙离子信号传导的途径：钠钾ATP酶α1和α2亚型对主动转运的抑制、肌醇三磷酸（IP3）生成的激活以及IP3受体（IP3R）电导的增加。一个基本预测是，钠钾ATP酶抑制有利于肌浆网钙离子储存的加载，而Src介导的IP3生成增加和IP3R致敏则有利于储存的耗竭。该模型预测，α2亚型抑制会产生胞质钙离子浓度（Ca2 +）升高的峰 - 平台模式，而α1亚型抑制则产生单相上升。哇巴因介导的IP3生成或IP3R电导增加对Ca2 +的影响取决于它们在细胞微区和整体细胞质之间的相对分布。模拟表明，IP3生成的细胞内定位是哇巴因可诱导的区室化钙离子浓度变化的关键决定因素。由于将对哇巴因敏感的α2亚型隔离到微区中，预计啮齿动物中α2亚型的抑制不会显著影响胞质钠浓度。模型模拟支持这样的假设，即当哇巴因的主要作用是抑制α2亚型钠转运从而增加钙离子加载到肌浆网储存中时，哇巴因可增强激动剂诱发的Ca2 +瞬变。
