Biology Reference
In-Depth Information
4. FUNCTIONAL ANALYSES OF ARRESTIN SIGNALING
PARADIGMS
We have so far described how the initial discovery of
b
-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 dis-
coveries, it has taken nearly a decade for this concept to reach the level of
common acceptance and translational therapeutic development.
26,83
At the
present time,
b
-arrestin signaling from GPCRs is the subject of standardized
analysis and industrial therapeutic creation. For example, several studies have
demonstrated the existence of idiosyncratic GPCR-associated
b
-arrestin
signaling paradigms that appear to control bone density regulation,
26,83
cell
proliferation,
146
and antipsychotic activity.
147
These physiological findings
have been supported by mechanistic studies, at the mass analytical level using
tissue-based transcriptomics,
26
phosphoproteomics,
148
MS-based direct
b
-arrestin interactomics,
149
or bioluminescence resonance energy
transfer-based network analysis.
150
These experiments have therefore
reinforced the existence of unique signaling activities emanating from
b
-arrestin-coupled GPCRs. With the demonstration of important and dis-
tinct physiological effects of
b
-arrestin signaling, via unique molecular
mechanisms, the logical progression from this has been the development
of GPCR ligands that demonstrate selective
in vitro
and
in vivo b
-arrestin
signaling-dependent efficacies.
26,83,151-155
In the previous sections, we have outlined many, but not all, of the
potentially productive analytical methodologies that can be applied to bio-
logical systems to increase the depth of our appreciation of the GPCR-based
b
-arrestin signaling at a systems level. The term
systems biology
is often
employed in a random manner that may or may not be entirely appropriate
for the specific study in question. A systems-level appreciation of any bio-
logical process often will seem antithetical to the majority of molecular biol-
ogists, as in its truest sense “systems” approaches do not place supreme
importance upon a single gene or protein. Systems-level signaling
approaches are inherently nonlinear and unbiased and therefore directly at
odds with the many years of reductionist one-gene/protein-centric peer-
reviewed science. Understanding biological processes at a systems-level is
therefore often considered nebulous and undirected compared to dogmatic
Search WWH ::
Custom Search