Systems Analysis of Arrestin Pathway Functions - Progress in Molecular Biology and Translational Science - page 416

CHAPTER SEVENTEEN

Systems Analysis of Arrestin
Pathway Functions

Stuart Maudsley * , Sana Siddiqui * , Bronwen Martin †
* Receptor Pharmacology Unit, National Institute on Aging, Baltimore, Maryland, USA
† Metabolism Unit, National Institute on Aging, Baltimore, Maryland, USA

Contents
1. G Protein-Coupled Receptor Signaling Activity 432

2. Signaling Diversity Among GPCRs 433

2.1 Accessory protein association 434

2.2 Arrestin-associated GPCR signaling 435

2.3 Signal integration and encryption 436

3. Systems Analysis of Receptor Signaling Systems 438

3.1 Transcriptomic analysis 440

3.2 Global proteomic analysis 443

3.3 Posttranslational proteomic analysis 446

3.4 Physical interactomic investigation 449

3.5 Bioinformatic interpretation 451

4. Functional Analyses of Arrestin Signaling Paradigms 457

5. Conclusions 459

Acknowledgments 459

References 459

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 combi-
nation 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 “ signa-
tures ” 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.