G-Protein Coupled Receptor Signaling Architecture of Mammalian Immune Cells

Abstract

A series of recent studies on large-scale networks of signaling and metabolic systems revealed that a certain network structure often called “bow-tie network” are observed. In signaling systems, bow-tie network takes a form with diverse and redundant inputs and outputs connected via a small numbers of core molecules. While arguments have been made that such network architecture enhances robustness and evolvability of biological systems, its functional role at a cellular level remains obscure. A hypothesis was proposed that such a network function as a stimuli-reaction classifier where dynamics of core molecules dictate downstream transcriptional activities, hence physiological responses against stimuli. In this study, we examined whether such hypothesis can be verified using experimental data from Alliance for Cellular Signaling (AfCS) that comprehensively measured GPCR related ligands response for B-cell and macrophage. In a GPCR signaling system, cAMP and Ca2+ act as core molecules. Stimuli-response for 32 ligands to B-Cells and 23 ligands to macrophages has been measured. We found that ligands with correlated changes of cAMP and Ca2+ tend to cluster closely together within the hyperspaces of both cell types and they induced genes involved in the same cellular processes. It was found that ligands inducing cAMP synthesis activate genes involved in cell growth and proliferation; cAMP and Ca2+ molecules that increased together form a feedback loop and induce immune cells to migrate and adhere together. In contrast, ligands without a core molecules response are scattered throughout the hyperspace and do not share clusters. G-protein coupling receptors together with immune response specific receptors were found in cAMP and Ca2+ activated clusters. Analyses have been done on the original software applicable for discovering ‘bow-tie’ network architectures within the complex network of intracellular signaling where ab initio clustering has been implemented as well. Groups of potential transcription factors for each specific group of genes were found to be partly conserved across B-Cell and macrophage. A series of findings support the hypothesis.

Comparing Label-Free Biosensors for Pharmacological Screening With Cell-Based Functional Assays

“…11 Dual coupling is increasingly being recognized as a common feature in GPCR signaling. 24,25 Each of these label-free instruments tested here offers the ability to detect multiple responses yet they differ in ability to distinguishing pathways, which leads to distinct advantages depending on the application. For example, CellKey offers clear advantages for comparing pathway bias of established ligands during secondary screening of HTS hits (CRF in Fig.…”

Cortical High-Density Counterstream Architectures

“…A core-periphery structure has been observed in other self-organized information-processing architectures, both human-made such as the World Wide Web (113) and the Internet (114, 115), and in biological networks, such as in metabolism (116, 117), the immune system (118), and cell signaling (119–121). The resulting bow tie is an evolutionarily favored structure for a wide variety of complex networks (122, 123), expressing the fact that functional or living systems have an input interface, a processing unit, and an output interface.…”

Recent Advances in Gut Nutrient Chemosensing

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