Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 469

“unnatural” ways, and their biological effects may be less predictable. The
same properties that make them valuable as potential therapeutics, that is, the
ability to qualitatively change GPCR signaling, may also make them more
prone to produce unanticipated effects.
4. THE CONSERVED ARRESTIN-DEPENDENT SIGNALING
REPERTOIRE
In the native context, GPCRs and their cognate ligands co-evolved to
control signaling in the most physiologically adaptive manner. Signaling,
reflected in the distribution of active states stabilized by the native ligand
and the efficiency with which these states couple the receptor to each of
its downstream effectors, is therefore “balanced” to meet the needs of the
organism. Biased agonists, on the other hand, alter the distribution of active
states. The resulting signals are not qualitatively different, but are “unbal-
anced” compared to the native ligand. 11 As these unbalanced signals prop-
agate, differences in the tissue response may arise from relatively subtle
differences in signal strength or the kinetics of pathway activation and deac-
tivation. Certainly, the presence of disease can cause adaptive responses to
become maladaptive, as in the case of endogenous catecholamine signaling
in the setting of congestive heart failure, 58 and this is one arena in which
biased agonists hold promise as therapeutics. 42,54 The ability to recalibrate
GPCR signaling to adapt to the needs of a perturbed system is something
that cannot be achieved using conventional agonist or antagonists.
Part of the solution to the screener's dilemma may lie in the study of con-
served arrestin signaling functions. If arrestin signaling affects a core set of bio-
logical processes in consistent ways, it may become easier to identify settings in
which accentuating or diminishing arrestin signaling would help to
“recalibrate” GPCR signaling to restore adaptive function. 11 To date, the
hypothesis that aspects of the arrestin signaling repertoire are conserved across
different GPCRs and tissues has not been systematically investigated. How-
ever, a review of the current literature (as presented in the preceding chapters
of this volume) does point to certain commonalities that help to define a
framework for understanding arrestin signaling at the biological process level.
4.1. GPCR desensitization
The most obvious conserved arrestin function is the negative regulation of
G protein signaling, through direct steric hindrance of the GPCR-G protein
interaction, mediation of receptor sequestration, and recruitment of second