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WIREs Syst Biol Med
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The structure of dynamic GPCR signaling networks

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G‐protein‐coupled receptors (GPCRs) stimulate signaling networks that control a variety of critical physiological processes. Static information on the map of interacting signaling molecules at the basis of many cellular processes exists, but little is known about the dynamic operation of these networks. Here we focus on two questions. First, Is the network architecture underlying GPCR‐activated cellular processes unique in comparison with others such as transcriptional networks? We discuss how spatially localized GPCR signaling requires uniquely organized networks to execute polarized cell responses. Second, What approaches overcome challenges in deciphering spatiotemporally dynamic networks that govern cell behavior? We focus on recently developed microfluidic and optical approaches that allow GPCR signaling pathways to be triggered and perturbed with spatially and temporally variant input while simultaneously visualizing molecular and cellular responses. When integrated with mathematical modeling, these approaches can help identify design principles that govern cell responses to extracellular signals. We outline why optical approaches that allow the behavior of a selected cell to be orchestrated continually are particularly well suited for probing network organization in single cells. WIREs Syst Biol Med 2014, 6:115–123. doi: 10.1002/wsbm.1249 This article is categorized under: Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models

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Comparison of gene regulatory networks with a GPCR network that regulates polarized cell behavior. The GPCR network structure includes dynamic links between network motifs that guide spatial response. The network motif shown is the incoherent feedforward loop (Box ) which becomes the LEGI motif (Box ) in the case of the migrating cell due to diffusion of the inhibitor to the back of the cell. Gray arrow denotes the direction of chemoattractant gradient.
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Activating G‐protein signaling with spatially localized discrete optical inputs. Macrophage‐like cells expressing blue opsin were optically activated at one end of a cell. The accumulation of PIP3 at the front of the cell exhibited a switch‐like behavior with increasing number of light pulses, and cell migration correlated with the steepest region of the response.
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Imaging single cell responses to dynamic inputs help to determine network structure. (a) Single cell imaging of GPCR‐stimulated Ras activation was used to determine the network motif that provides adaptation. The incoherent feedforward loop (IFFL) and the integral feedback control motifs both are capable of perfect adaptation, but only IFFL responds to a wide range of agonist concentrations with similar adaptation kinetics as was found experimentally. (b) A phase locking method was used to test different network models for the Gq stimulated calcium response. Subthreshold calcium spikes observed by the phase locking method helped to differentiate between models that could not be distinguished in experiments that used a step increase in agonist concentration.
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Biological Mechanisms > Cell Signaling
Models of Systems Properties and Processes > Mechanistic Models

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