Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 475

mice showed significantly higher peritoneal and pulmonary neutrophil accu-
mulation than wild-type controls. 101 Thus, while it is clear that arrestins are
critical mediators of chemotaxis in cells of the immune system, their overall
functions in modulating immune responses are quite complex.
5. CONCLUSIONS
Conventional receptor theory predicts that GPCRs exist in spontane-
ous equilibrium between “inactive” and “active” states that are stabilized by
ligand binding, leading to increases or decreases in receptor coupling to its
intracellular effectors. Agonists increase the proportion of receptors in the
active state and antagonists decrease it, but the receptor alone specifies which
pathways are activated. What the concepts of pluridimensional efficacy and
functional selectivity have taught us is that receptors have multiple active
states with different signaling capacity, and structurally distinct ligands have
the ability to stabilize these active states in different proportions compared
with the native ligand. In other words, the ligand-receptor complex, not the
receptor alone, determines signal output. And if the ligand-receptor com-
plex defines the signaling, then biased ligands can create, in effect, new
receptors whose functionality is both unknown and possibly unique to each
ligand-receptor pair.
At present, we face a gap between the in vitro characterization of ligand
bias and the unpredictability of its in vivo effects. The physiological effects of
conventional agonist or antagonist ligands can largely be predicted based on
the physiological properties of the native ligand. But if every biased ligand-
GPCR pair is a functionally distinct entity with the potential to influence
biological systems in unique ways, then the discovery of therapeutically use-
ful biased agonists becomes a matter of trial and error. The screener cannot
know which in vitro properties of a biased agonist will predict the desired
in vivo biological response. With respect to arrestin-selective biased ligands,
additional work is needed to determine the most physiologically relevant
arrestin-mediated pathways in vivo, and the extent to which these pathways
are conserved between different GPCRs and different tissues. The facts that
there are only two non-visual arrestins, they are ubiquitously expressed out-
side the retina, and they interact with the vast majority of GPCRs, at least
offer hope that it will become possible to relate the effects of arrestin-
selective agonists in vitro and in vivo . Within such a framework, it may be
easier to capitalize on the promise of biased agonism.