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its expression in cells directs the receptor toward degradative pathways rather
than the naturally occurring recycling and resensitization.
15
4. CONCLUSIONS
Arrestin function in GPCR desensitization, sequestration, and vesic-
ular trafficking has been studied intensively over decades. Thereby,
researchers worldwide were able to establish a prototypical mechanism on
how arrestin regulates each of these steps individually. Nonetheless, excep-
tions to the predominant rules governing the regulation of GPCRs will
always exist and may provide advantages for the development of new ther-
apeutics to treat disease. It is increasingly becoming evident that GPCRs are
not the only substrates for
b
-arrestin. The
b
-arrestin interaction network is
far more complex than assumed 20 years ago. Arrestins are now recognized
as key scaffolding molecules that connect membrane receptors to multiple
cytosolic proteins that use the
b
-arrestin-bound receptor as the platform
for assembling multiple protein signaling complexes. Thus,
b
-arrestins have
the remarkable ability both to regulate the kinetics and the extent of GPCR
cellular activity at the level of desensitization, internalization, and subse-
quent intracellular fate, and control the activation and compartmentation
of a wide variety of G protein-independent signal transduction cascades.
ACKNOWLEDGMENTS
This work was supported by an operating grant to S. S. G. F. from the Canadian Institutes of
Health Research (CIHR) (MOP-119437, MOP-62738, and MOP-111093) and a Navigator
Grant from the Huntington's Society of Canada. S. S. G. F. also holds a Tier I Canada
Research Chair in Molecular Neurobiology and is a Career Investigator of the Heart and
Stroke Foundation of Ontario.
REFERENCES
1.
Neer EJ. Heterotrimeric G proteins: organizers of
transmembrane signals.
Cell
.
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