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Cells navigate with a local-excitation, global-inhibition-biased excitable network.

ABSTRACT: Cells have an internal compass that enables them to move along shallow chemical gradients. As amoeboid cells migrate, signaling events such as Ras and PI3K activation occur spontaneously on pseudopodia. Uniform stimuli trigger a symmetric response, whereupon cells stop and round up; then localized patches of activity appear as cells spread. Finally cells adapt and resume random migration. In contrast, chemotactic gradients continuously direct signaling events to the front of the cell. Local-excitation, global-inhibition (LEGI) and reaction-diffusion models have captured some of these features of chemotaxing cells, but no system has explained the complex response kinetics, sensitivity to shallow gradients, or the role of recently observed propagating waves within the actin cytoskeleton. We report here that Ras and PI3K activation move in phase with the cytoskeleton events and, drawing on all of these observations, propose the LEGI-biased excitable network hypothesis. We formulate a model that simulates most of the behaviors of chemotactic cells: In the absence of stimulation, there are spontaneous spots of activity. Stimulus increments trigger an initial burst of patches followed by localized secondary events. After a few minutes, the system adapts, again displaying random activity. In gradients, the activity patches are directed continuously and selectively toward the chemoattractant, providing an extraordinary degree of amplification. Importantly, by perturbing model parameters, we generate distinct behaviors consistent with known classes of mutants. Our study brings together heretofore diverse observations on spontaneous cytoskeletal activity, signaling responses to temporal stimuli, and spatial gradient sensing into a unified scheme.

SUBMITTER: Xiong Y

PROVIDER: S-EPMC2951443 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Cells navigate with a local-excitation, global-inhibition-biased excitable network.

Xiong Yuan Y Huang Chuan-Hsiang CH Iglesias Pablo A PA Devreotes Peter N PN

Proceedings of the National Academy of Sciences of the United States of America 20100923 40

Cells have an internal compass that enables them to move along shallow chemical gradients. As amoeboid cells migrate, signaling events such as Ras and PI3K activation occur spontaneously on pseudopodia. Uniform stimuli trigger a symmetric response, whereupon cells stop and round up; then localized patches of activity appear as cells spread. Finally cells adapt and resume random migration. In contrast, chemotactic gradients continuously direct signaling events to the front of the cell. Local-exci ...[more]

PMID: 20864631

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Project description:Biological excitable media, such as cardiac or neural cells and tissue, exhibit memory in which a change in the present excitation may affect the behaviors in the next excitation. For example, a change in calcium (Ca2+) concentration in a cell in the present excitation may affect the Ca2+ dynamics in the next excitation via bi-directional coupling between voltage and Ca2+, forming a delayed feedback loop. Since the Ca2+ dynamics inside the excitable cells are spatiotemporal while the membrane voltage is a global signal, the feedback loop is then a delayed global feedback (DGF) loop. In this study, we investigate the roles of DGF in the genesis and stability of spatiotemporal excitation patterns in periodically-paced excitable media using mathematical models with different levels of complexity: a model composed of coupled FitzHugh-Nagumo units, a 3-dimensional physiologically-detailed ventricular myocyte model, and a coupled map lattice model. We investigate the dynamics of excitation patterns that are temporal period-2 (P2) and spatially concordant or discordant, such as subcellular concordant or discordant Ca2+alternans in cardiac myocytes or spatially concordant or discordant Ca2+ and repolarization alternans in cardiac tissue. Our modeling approach allows both computer simulations and rigorous analytical treatments, which lead to the following results and conclusions. When DGF is absent, concordant and discordant P2 patterns occur depending on initial conditions with the discordant P2 patterns being spatially random. When the DGF is negative, only concordant P2 patterns exist. When the DGF is positive, both concordant and discordant P2 patterns can occur. The discordant P2 patterns are still spatially random, but they satisfy that the global signal exhibits a temporal period-1 behavior. The theoretical analyses of the coupled map lattice model reveal the underlying instabilities and bifurcations for the genesis, selection, and stability of spatiotemporal excitation patterns.

Dataset Information

Cells navigate with a local-excitation, global-inhibition-biased excitable network.

Publications

Cells navigate with a local-excitation, global-inhibition-biased excitable network.

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