Systems Analysis of Arrestin Pathway Functions - Progress in Molecular Biology and Translational Science - page 419

in the isolation of unique arrestin signaling functionalities, as well as for
arrestin-dependent signaling discovery paradigms.
2.1. Accessory protein association
GPCRs demonstrate stable interactions with multiple juxta- or intra-
membrane accessory proteins that serve to regulate the parent receptor
structure, confer ligand interaction specificity, and regulate the subsequent
association with signaling cascades. The pharmacological structure of the
receptor with its specific accessory protein coterie forms a de facto novel
receptor structure, that is, the receptorsome. Receptorsome creation facili-
tates multiple aspects of signal preorganization as well as the maintenance
of transduction efficiency, specificity, kinetic modality, and dynamic feed-
back regulation. In addition, specific receptorsome entities are differentially
associated with various targeting mechanisms to subcellular compartments
(endoplasmic reticulum, Golgi apparatus) as well as diverse endocytic,
recycling, and degradative fates of the parent GPCR. 27-29 While many
of these accessory protein associations can add texture to GPCR-G
protein-mediated signal transduction, a small subset of the accessory pro-
teins can also engender the creation of G protein-independent signaling
events from the parent GPCR. One of the most important functional pro-
tein constituents of many receptorsomes is the arrestins. A considerable body
of data now exists to suggest that arrestin-mediated GPCR signaling is one
of the most important G protein-independent receptor signaling
modalities. 30-33 The demonstration of discrete receptorsome structures,
linked to unique signaling effects, now strongly reinforces the previously
developed concept of agonist-selective trafficking of receptor signaling.
In this agonist trafficking paradigm, specific ligands may select between
the de facto variants of active receptorsome conformations and induce only
a subset of the possible total response profile. Such diversity in agonistic
behavior presents the opportunity to develop drugs that change the quality,
as well as the quantity, of response efficacy. As a more comprehensive under-
standing of the complexity of GPCR signaling is developed, the rational
design of ligands possessing increased specific efficacy and attenuated side
effects may become the standard mode of drug development. This challenge
is currently being spearheaded with the de novo development of biased
GPCR ligands that target specifically arrestin-associated receptorsome enti-
ties. 18,26,34 Given the potential therapeutic importance of these advances, we