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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 signal-
ing factors, to preorganized
encrypton
-mediated signaling paradigms.
81
We,
therefore, consider that GPCR signaling systems possess far more func-
tional components than those identified in the early
two-state
models of
receptor signaling. The ability to identify the multiple protein components
of these increasingly complex signaling paradigms is vital for the future of
translational GPCR research. Hence GPCRs are thought now to exist, in a
functional sense, as higher-order receptor structures grouped into a variety
of substrate-specific isoforms that are coupled to preassembled signal trans-
duction cascades consisting of GPCR subtype-specific, stable multiprotein
signaling complexes that possess distinct subcellular targeting mecha-
nisms.
1,82
As we have previously described, these associated protein signal-
ing complexes, for example,
b
-arrestin-centered
encryptons
, can describe
and coordinate a specific signaling modality that targets a selective tran-
scriptional or translational target.
26,56-59,83
The
b
-arrestin- versus G -
protein-mediated signal bifurcation from the
parent
GPCR represents a
simple mechanism to assess the now diverse and highly complex down-
stream signaling network. G protein signaling is strongly associated with
molecular processes that regulate intermediary cell metabolism, for exam-
ple, calcium mobilization, or cAMP accumulation. This rapid form of sig-
naling, with transient levels of stimulus and reflex tachyphylaxis, is well
suited to the G protein paradigm as the temporal nature of the signaling
output is reflected by the transient nature of the GPCR-G protein inter-
action kinetics.
84
In contrast, the interaction kinetics of
b
-arrestins with
GPCRs are slower and therefore indicate a preference for the regulation
of long-term signaling paradigms that involve more profound cellular
effects, for example, genomic transcription and protein translation. This
development in the appreciation of GPCR signaling activity has therefore
necessitated an appreciation of GPCR signaling at a functional genomic
and proteomic level. With this conceptual advance, there is therefore an
inherent increase in the potential complexity of GPCR signaling systems.
While increases in systems complexity are often seen as potential hin-
drances to pharmacological research, quite the reverse is true. Indeed,
the more subtle our appreciation of the intricate nature of GPCR signaling
mechanisms and their contextual variety, then the more selective and spe-
cific rationally designed pharmacotherapies may become.
1,17,85,86
Thus,
investigation of signaling paradigms with mass analytical genomic/proteo-
mic technologies has forced us to consider that physiological processes/
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