Cellular Ability to Sense Spatial Gradients in the Presence of Multiple Competitive Ligands

Many eukaryotic and prokaryotic cells can exhibit remarkable sensing ability under small gradient of chemical compound. In this study, we approach this phenomenon by considering the contribution of multiple ligands to the chemical kinetics within Michaelis-Menten model. This work was inspired by the recent theoretical findings from Bo Hu et al. [Phys. Rev. Lett. 105, 048104 (2010)], our treatment with practical binding energies and chemical potential provides the results which are consistent with experimental observations.Comment: 5 pages, 4 figure

Phosphorylation of chemoattractant receptors is not essential for chemotaxis or termination of G-protein-mediated responses

In several G-protein-coupled signaling systems, ligand-induced receptor phosphorylation by specific kinases is suggested to lead to desensitization via mechanisms including receptor/G-protein uncoupling, receptor internalization, and receptor down-regulation. We report here that elimination of phosphorylation of a chemoattractant receptor of Dictyostelium, either by site-directed substitution of the serines or by truncation of the C-terminal cytoplasmic domain, completely prevented agonist-induced loss of ligand binding but did not impair the adaptation of several receptor-mediated responses including the activation of adenylyl and guanylyl cyclases and actin polymerization, In addition, the phosphorylation deficient receptors were capable of mediating chemotaxis, aggregation, and differentiation. We propose that for chemoattractant receptors agonist-induced phosphorylation regulates surface binding activity but other phosphorylation-independent mechanisms mediate response adaptation

Streaming instability of slime mold amoebae: An analytical model

During the aggregation of amoebae of the cellular slime mould Dictyostelium, the interaction of chemical waves of the signaling molecule cAMP with cAMP-directed cell movement causes the breakup of a uniform cell layer into branching patterns of cell streams. Recent numerical and experimental investigations emphasize the pivotal role of the cell-density dependence of the chemical wave speed for the occurrence of the streaming instability. A simple, analytically tractable, model of Dictyostelium aggregation is developed to test this idea. The interaction of cAMP waves with cAMP-directed cell movement is studied in the form of coupled dynamics of wave front geometries and cell density. Comparing the resulting explicit instability criterion and dispersion relation for cell streaming with the previous findings of model simulations and numerical stability analyses, a unifying interpretation of the streaming instability as a cAMP wave-driven chemotactic instability is proposed

Chemotaxis: a feedback-based computational model robustly predicts multiple aspects of real cell behaviour

The mechanism of eukaryotic chemotaxis remains unclear despite intensive study. The most frequently described mechanism acts through attractants causing actin polymerization, in turn leading to pseudopod formation and cell movement. We recently proposed an alternative mechanism, supported by several lines of data, in which pseudopods are made by a self-generated cycle. If chemoattractants are present, they modulate the cycle rather than directly causing actin polymerization. The aim of this work is to test the explanatory and predictive powers of such pseudopod-based models to predict the complex behaviour of cells in chemotaxis. We have now tested the effectiveness of this mechanism using a computational model of cell movement and chemotaxis based on pseudopod autocatalysis. The model reproduces a surprisingly wide range of existing data about cell movement and chemotaxis. It simulates cell polarization and persistence without stimuli and selection of accurate pseudopods when chemoattractant gradients are present. It predicts both bias of pseudopod position in low chemoattractant gradients and-unexpectedly-lateral pseudopod initiation in high gradients. To test the predictive ability of the model, we looked for untested and novel predictions. One prediction from the model is that the angle between successive pseudopods at the front of the cell will increase in proportion to the difference between the cell's direction and the direction of the gradient. We measured the angles between pseudopods in chemotaxing Dictyostelium cells under different conditions and found the results agreed with the model extremely well. Our model and data together suggest that in rapidly moving cells like Dictyostelium and neutrophils an intrinsic pseudopod cycle lies at the heart of cell motility. This implies that the mechanism behind chemotaxis relies on modification of intrinsic pseudopod behaviour, more than generation of new pseudopods or actin polymerization by chemoattractant

Self-organized Vortex State in Two-dimensional Dictyostelium Dynamics

We present results of experiments on the dynamics of Dictyostelium discoideum in a novel set-up which constraints cell motion to a plane. After aggregation, the amoebae collect into round ''pancake" structures in which the cells rotate around the center of the pancake. This vortex state persists for many hours and we have explicitly verified that the motion is not due to rotating waves of cAMP. To provide an alternative mechanism for the self-organization of the Dictyostelium cells, we have developed a new model of the dynamics of self-propelled deformable objects. In this model, we show that cohesive energy between the cells, together with a coupling between the self-generated propulsive force and the cell's configuration produces a self-organized vortex state. The angular velocity profiles of the experiment and of the model are qualitatively similar. The mechanism for self-organization reported here can possibly explain similar vortex states in other biological systems.Comment: submitted to PRL; revised version dated 3/8/9

Modeling Cell Gradient Sensing and Migration in Competing Chemoattractant Fields

Directed cell migration mediates physiological and pathological processes. In particular, immune cell trafficking in tissues is crucial for inducing immune responses and is coordinated by multiple environmental cues such as chemoattractant gradients. Although the chemotaxis mechanism has been extensively studied, how cells integrate multiple chemotactic signals for effective trafficking and positioning in tissues is not clearly defined. Results from previous neutrophil chemotaxis experiments and modeling studies suggested that ligand-induced homologous receptor desensitization may provide an important mechanism for cell migration in competing chemoattractant gradients. However, the previous mathematical model is oversimplified to cell gradient sensing in one-dimensional (1-D) environment. To better understand the receptor desensitization mechanism for chemotactic navigation, we further developed the model to test the role of homologous receptor desensitization in regulating both cell gradient sensing and migration in different configurations of chemoattractant fields in two-dimension (2-D). Our results show that cells expressing normal desensitizable receptors preferentially orient and migrate toward the distant gradient in the presence of a second local competing gradient, which are consistent with the experimentally observed preferential migration of cells toward the distant attractant source and confirm the requirement of receptor desensitization for such migratory behaviors. Furthermore, our results are in qualitative agreement with the experimentally observed cell migration patterns in different configurations of competing chemoattractant fields