Laub M T, Loomis W F
Center for Molecular Genetics, Department of Biology, University of California, San Diego, La Jolla, California 92093, USA.
Mol Biol Cell. 1998 Dec;9(12):3521-32. doi: 10.1091/mbc.9.12.3521.
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.
已发现一个相互作用的蛋白质网络，它可以解释在盘基网柄菌细胞发育开始4小时后，在同质细胞群体中观察到的腺苷酸环化酶活性的自发振荡。先前的生化分析表明，当细胞外3',5'-环磷酸腺苷（cAMP）与表面受体CAR1结合时，腺苷酸环化酶和丝裂原活化蛋白激酶ERK2会被短暂激活。细胞内cAMP浓度的升高会激活蛋白激酶A，使其抑制ERK2，并导致CAR1失去配体结合能力。ERK2会磷酸化cAMP磷酸二酯酶REG A，从而降低细胞内cAMP的浓度。一种分泌型磷酸二酯酶会在脉冲之间降低细胞外cAMP的浓度。描述这些活动的一系列非线性微分方程的数值解忠实地解释了观察到的cAMP的周期性变化。网络中每个组件的活性对于产生振荡行为都是必需的；然而，该模型具有鲁棒性，因为连接这些活动的动力学常数有25倍的变化对预测频率只有微小影响。此外，持续高水平的细胞外cAMP会导致衰减，而短暂的cAMP脉冲可以提前或延迟相位，从而使相互作用的细胞被同步化。
