Moghe P V, Tranquillo R T
Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis 55455.
Bull Math Biol. 1994 Nov;56(6):1041-93. doi: 10.1007/BF02460287.
Mammalian white blood cells are known to bias the direction of their movement along concentration gradients of specific chemical stimuli, a phenomenon called chemotaxis. Chemotaxis of leukocyte cells is central to the acute inflammatory response in living organisms and other critical physiological functions. On a molecular level, these cells sense the stimuli termed chemotactic factor (CF) through specific cell surface receptors that bind CF molecules. This triggers a complex signal transduction process involving intracellular biochemical pathways and biophysical events, eventually leading to the observable chemotactic response. Several investigators have shown theoretically that statistical fluctuations in receptor binding lead to "noisy" intracellular signals, which may explain the observed imperfect chemotactic response to a CF gradient. The most recent dynamic model (Tranquillo and Lauffenburger, J. Math. Biol. 25, 229-262. 1987) couples a scheme for intracellular signal transduction and cell motility response with fluctuations in receptor binding. However, this model employs several assumptions regarding receptor dynamics that are now known to be oversimplifications. We extend the earlier model by accounting for several known and speculated chemotactic receptor dynamics, namely, transient G-protein signaling, cytoskeletal association, and receptor internalization and recycling, including statistical fluctuations in the numbers of receptors among the various states. Published studies are used to estimate associated constants and ensure the predicted receptor distribution is accurate. Model analysis indicates that directional persistence in uniform CF concentrations is enhanced by increasing rate constants for receptor cytoskeletal inactivation, ternary complex dissociation, and binary complex dissociation, and by decreasing rate constants for receptor internalization and recycling. For most rate constants, we have detected an optimal range that maximizes orientation bias in CF gradients. We have also examined different desensitization and receptor recycling mechanisms that yield experimentally documented orientation behavior. These yield novel insights into the relationship between receptor dynamics and leukocyte chemosensory movement behavior.
哺乳动物的白细胞已知会沿着特定化学刺激的浓度梯度偏向其运动方向，这种现象称为趋化性。白细胞的趋化性是生物体急性炎症反应和其他关键生理功能的核心。在分子水平上，这些细胞通过结合趋化因子（CF）分子的特定细胞表面受体来感知刺激。这触发了一个复杂的信号转导过程，涉及细胞内生化途径和生物物理事件，最终导致可观察到的趋化反应。几位研究者从理论上表明，受体结合中的统计波动会导致“嘈杂的”细胞内信号，这可能解释了观察到的对CF梯度的不完美趋化反应。最新的动态模型（Tranquillo和Lauffenburger，《数学生物学杂志》25，229 - 262，1987年）将细胞内信号转导和细胞运动反应方案与受体结合的波动耦合在一起。然而，该模型采用了一些关于受体动力学的假设，现在已知这些假设过于简化。我们通过考虑几种已知和推测的趋化受体动力学来扩展早期模型，即瞬时G蛋白信号传导、细胞骨架关联以及受体内化和再循环，包括不同状态下受体数量的统计波动。已发表的研究用于估计相关常数，并确保预测的受体分布准确。模型分析表明，通过增加受体细胞骨架失活、三元复合物解离和二元复合物解离的速率常数，以及降低受体内化和再循环的速率常数，可以增强在均匀CF浓度下的方向持续性。对于大多数速率常数，我们检测到一个最佳范围，该范围能使CF梯度中的方向偏差最大化。我们还研究了产生实验记录的定向行为的不同脱敏和受体再循环机制。这些为受体动力学与白细胞化学感应运动行为之间的关系提供了新的见解。
