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effective keystones. These keystones profoundly enhance and facilitate rapid
and robust connections between disparate parts of a network constellation
and, as such, can be considered as functional “shortcuts” in the complex
system. 156 It has been demonstrated, using mathematical modeling of graph
and network theories, that even in networks containing thousands to mil-
lions of nodes, surprisingly few (5-10) “shortcuts” (keystones) are required
to facilitate rapid transfer across even the largest of systems. 156 Considering
the outlined functional roles and activities of b -arrestin signaling paradigms,
the ability of this molecule to acts as a functional keystone in GPCR cell
signaling networks may be fully appreciated in the near future with the
diligent application of a systems-level conceptual approach.
5. CONCLUSIONS
The demonstration that b -arrestin-regulated signaling pathways ema-
nate 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 the creation
of idiosyncratic “patterns” of signaling activity instead. The b -arrestin
GPCR signaling paradigm is currently one of the most prominent physio-
logical processes that has been subjected to this novel form of systems-level
analysis. It is hoped that the eventual results of the research carried out in this
emerging field will eventually lead to the creation of a new b -arrestin-
biased, effective, and unique GPCR pharmacopeia.
ACKNOWLEDGMENTS
This work was supported by the Intramural Program of the National Institute on Aging and
National Institutes of Health.
REFERENCES
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action and therapeutics: relevance of novel concepts in G-protein-coupled receptor
and signal transduction pharmacology. Br J Clin Pharmacol . 2004;57:373- 387.
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