A molecular network that produces spontaneous oscillations in excitable cells of Dictyostelium
A molecular network that produces spontaneous oscillations in excitable cells of Dictyostelium
复制标题
DOI：
10.1091/mbc.9.12.3521
复制
发表时间：
1998-12-01
影响因子：
3.3
通讯作者：
Loomis, WF
中科院分区：
文献类型：
--
作者：
Laub, MT;Loomis, WF
已经发现了一个相互作用的蛋白质网络，可以解释腺苷酸环化酶活性的自发振荡，观察到在同源群体的Dictyosteoblasts细胞4小时后开始发展。先前的生物化学测定已经表明，当细胞外腺苷3 '，5'-环一磷酸（cAMP）结合表面受体CAR 1时，腺苷酸环化酶和MAP激酶ERK 2被瞬时激活。cAMP内部浓度的升高激活蛋白激酶A，从而抑制ERK 2并导致CAR 1的配体结合丧失。ERK 2使cAMP磷酸二酯酶REG A磷酸化，从而降低cAMP的内部浓度。分泌的磷酸二酯酶降低脉冲之间的外部cAMP浓度。一系列描述这些活动的非线性微分方程的数值解忠实地解释了所观察到的cAMP的周期性变化。每个组件的活动是网络产生振荡行为所必需的;然而，该模型是稳健的，因为连接活动的动力学常数的25倍变化对预测频率只有很小的影响。此外，恒定的高水平的外部cAMP导致衰减，而cAMP的短暂脉冲可以提前或延迟相位，使得相互作用的细胞被夹带。
A network of interacting proteins has been found that can account for the spontaneous oscillations in adenylyl cyclase activity that are observed in homogenous populations of Dictyostelium cells 4 h after the initiation of development. Previous biochemical assays have shown that when extracellular adenosine 3',5'-cyclic monophosphate (cAMP) binds to the surface receptor CAR1, adenylyl cyclase and the MAP kinase ERK2 are transiently activated. A rise in the internal concentration of cAMP activates protein kinase A such that it inhibits ERK2 and leads to a loss-of-ligand binding by CAR1. ERK2 phosphorylates the cAMP phosphodiesterase REG A that reduces the internal concentration of cAMP. A secreted phosphodiesterase reduces external cAMP concentrations between pulses. Numerical solutions to a series of nonlinear differential equations describing these activities faithfully account for the observed periodic changes in cAMP. The activity of each of the components is necessary for the network to generate oscillatory behavior; however, the model is robust in that 25-fold changes in the kinetic constants linking the activities have only minor effects on the predicted frequency. Moreover, constant high levels of external cAMP lead to attenuation, whereas a brief pulse of cAMP can advance or delay the phase such that interacting cells become entrained.