Simulations of inositol phosphate metabolism and its interaction with InsP3-mediated calcium release
Simulations of inositol phosphate metabolism and its interaction with InsP3-mediated calcium release
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DOI：
10.1016/s0006-3495(02)73901-5
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发表时间：
2002-09-01
影响因子：
3.4
通讯作者：
Bhalla, US
中科院分区：
文献类型：
--
作者：
Mishra, J;Bhalla, US
肌醇磷酸是多种细胞外信号的第二信使。磷脂酶c介导的磷脂酰肌醇二磷酸水解产生Ins(1,4,5)P-3，通过调节钙从内部储存中释放触发许多细胞过程。Ins(1,4,5)P-3信号与一系列磷酸酶和激酶的复杂代谢级联相耦合。这些酶产生一系列磷酸肌醇衍生物，其中许多具有自身的信号作用。我们整合了已发表的生化数据，建立了InsP(3)代谢的质量作用模型。该模型包括目前已知的大多数相互作用的磷酸肌醇。我们已经使用这个模型来研究激活磷脂酶C的g蛋白偶联受体刺激对肌醇磷酸的影响。我们还监测了代谢级联如何与Ins(1,4,5) p -3介导的钙释放相互作用。我们发现大多数肌醇磷酸盐的时间动态受到精心设计的网络的强烈影响。我们还表明Ins(1,3,4,5)P-4在InsP(3)动力学中起关键作用，并允许配对脉冲促进钙释放。钙振荡在部分代谢网络中产生振荡反应，并依次被InsP代谢暂时调节(3)。
Inositol phosphates function as second messengers for a variety of extracellular signals. Ins(1,4,5)P-3 generated by phospholipase C-mediated hydrolysis of phosphatidylinositol bisphosphate, triggers numerous cellular processes by regulating calcium release from internal stores. The Ins(1,4,5)P-3 signal is coupled to a complex metabolic cascade involving a series of phosphatases and kinases. These enzymes generate a range of inositol phosphate derivatives, many of which have signaling roles of their own. We have integrated published biochemical data to build a mass action model for InsP(3) metabolism. The model includes most inositol phosphates that are currently known to interact with each other. We have used this model to study the effects of a G-protein coupled receptor stimulus that activates phospholipase C on the inositol phosphates. We have also monitored how the metabolic cascade interacts with Ins(1,4,5)P-3-mediated calcium release. We find temporal dynamics of most inositol phosphates to be strongly influenced by the elaborate networking. We also show that Ins(1,3,4,5)P-4 plays a key role in InsP(3) dynamics and allows for paired pulse facilitation of calcium release. Calcium oscillations produce oscillatory responses in parts of the metabolic network and are in turn temporally modulated by the metabolism of InsP(3).