G Protein–Coupled Receptor Signaling Networks from a Systems Perspective

Abstract

The signal-transduction network of a mammalian cell integrates internal and external cues to initiate adaptive responses. Among the cell-surface receptors are the G protein-coupled receptors (GPCRs), which have remarkable signal-integrating capabilities. Binding of extracellular signals stabilizes intracellular-domain conformations that selectively activate intracellular proteins. Hereby, multiple signaling routes are activated simultaneously to degrees that are signal-combination dependent. Systems-biology studies indicate that signaling networks have emergent processing capabilities that go far beyond those of single proteins. Such networks are spatiotemporally organized and capable of gradual, oscillatory, all-or-none, and subpopulation-generating responses. Proteinprotein interactions, generating feedback and feedforward circuitry, are generally required for these spatiotemporal phenomena. Understanding of information processing by signaling networks therefore requires network theories in addition to biochemical and biophysical concepts. Here we review some of the key signaling systems behaviors that have been discovered recurrently across signaling networks. We emphasize the role of GPCRs, so far underappreciated receptors in systems-biology research.

A perspective on multi‐target drug discovery and design for complex diseases

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Ehrlichia chaffeensis Tandem Repeat Effector Targets Differentially Influence Infection

“…These results support the importance of many conserved cellular signaling pathways in ehrlichial survival. For example, G-protein coupled receptor (GPCR) signaling involves a variety of ligands and stimuli and can regulate a highly interconnected network of signal transductions and cellular responses (Roth et al, 2015). We found that six TRP120-interacting proteins including ADAM17, A kinase anchor protein 2 (AKAP2), C-X-C motif chemokine ligand 12 (CXCL12), G protein subunit alpha i2 (GNAI2), G protein pathway suppressor 1 (GPS1), and phosphodiesterase 1B (PDE1B), and one TRP47-interacting protein GNB1 are involved in GPCR signaling.…”