Chapter Seventeen - Systems Analysis of Arrestin Pathway Functions

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Abstract

To fully appreciate the diversity and specificity of complex cellular signaling events, such as arrestin-mediated signaling from G protein-coupled receptor activation, a complex systems-level investigation currently appears to be the best option. A rational combination of transcriptomics, proteomics, and interactomics, all coherently integrated with applied next-generation bioinformatics, is vital for the future understanding of the development, translation, and expression of GPCR-mediated arrestin signaling events in physiological contexts. Through a more nuanced, systems-level appreciation of arrestin-mediated signaling, the creation of arrestin-specific molecular response “signatures” should be made simple and ultimately amenable to drug discovery processes. Arrestin-based signaling paradigms possess important aspects, such as its specific temporal kinetics and ability to strongly affect transcriptional activity, that make it an ideal test bed for next-generation of drug discovery bioinformatic approaches such as multi-parallel dose–response analysis, data texturization, and latent semantic indexing-based natural language data processing and feature extraction.

Section snippets

G Protein-Coupled Receptor Signaling Activity

G protein-coupled receptor (GPCR)-mediated signaling represents one of the most fundamental physiological processes. GPCR signaling has been demonstrated to regulate almost all forms of cellular communication, while utilizing an incredibly diverse series of functional mechanisms to do so.1 As GPCR biology regulates the vast majority of physiological processes, it is unsurprising that nearly half of all current pharmacotherapeutics target this class of proteins.2 Historically, therapeutic agents

Signaling Diversity Among GPCRs

Aided by advances in technology and receptor theory development, our current appreciation of the multiple molecular nuances in GPCR signaling has expanded dramatically.18, 19, 20 Despite their G protein-biased description, their resultant spectrum of signaling output is unlikely to be solely G protein dependent. Multiple avenues of investigation have shown that GPCR cellular signaling exhibits considerably greater diversity and texture than previously appreciated.17, 21, 22 As we have

Systems Analysis of Receptor Signaling Systems

The field of GPCR signal transduction over the past decade has begun to efficiently and productively interact with the mass data analytical realms of genomic, proteomic, and metabolomic analyses.20 The consideration of the nature of signal transduction systems has moved away from linear signaling cascades, controlled by “Brownian” modes of motion of individual signaling factors, to preorganized encrypton-mediated signaling paradigms.81 We, therefore, consider that GPCR signaling systems possess

Functional Analyses of Arrestin Signaling Paradigms

We have so far described how the initial discovery of β-arrestin-mediated GPCR signaling activity was able to uncover an entirely new era of receptor signaling.30 The demonstration that the “desensitized” GPCR was indeed still active revealed the presence of a previously unseen spectrum of GPCR signaling activity. As with many paradigm-creating discoveries, it has taken nearly a decade for this concept to reach the level of common acceptance and translational therapeutic development.26, 83 At

Conclusions

The demonstration that β-arrestin-regulated signaling pathways emanate from GPCRs represented a significant shift, not just for cell signaling research, but for our understanding of the diversity of signaling systems and for the rational design of selective, discrete therapeutics. Rather than considering signaling systems as linear pathways composed of a simple sequence of kinases and substrates, applying a systems-level investigation has led to the appreciation that GPCR signaling engenders

Acknowledgments

This work was supported by the Intramural Program of the National Institute on Aging and National Institutes of Health.

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