Systems Analysis of Arrestin Pathway Functions - Progress in Molecular Biology and Translational Science - page 418

GPCRs may be largely controlled by idiosyncratic stable protein-protein
interactions that the GPCR engages in to generate its eventual downstream
signaling spectrum. The nature and stoichiometry of these de facto “distinct”
GPCR isoforms represent the most important new frontier of GPCR ther-
apeutic research. Creation of the GPCR isoform ensemble in cells or tissues is
likely to be microdomain, cell/tissue type, and temporally sensitive. The
creation of these plastic and diverse signaling GPCR isoforms, therefore,
opens up the potential for the development of drug compounds with tai-
lored and nuanced forms of pharmacological efficacy profiles. 15,16,12,17
Therefore, while we could consider each GPCR-interacting ligand with
a generic phrase, such as “agonist,” the true pharmacological nature of
the efficacy of these “agonists” is in fact multidimensional and contextually
sensitive.
2. SIGNALING DIVERSITY AMONG GPCRs
Aided by advances in technology and receptor theory development,
our current appreciation of the multiple molecular nuances in GPCR
signaling has expanded dramatically. 18-20 Despite their G protein-biased
description, their resultant spectrum of signaling output is unlikely to be
solely G protein dependent. Multiple avenues of investigation have shown
that GPCR cellular signaling exhibits considerably greater diversity and
texture than previously appreciated. 17,21,22 As we have previously described,
a considerable degree of GPCR signaling diversity arises from the ability of
receptors to adopt multiple “active” states that are created by a wide range of
stable juxtamembrane protein-protein interactions. These GPCR signaling
isoforms can: exhibit distinct effector-coupling profiles; describe receptor
dimers that exhibit unique pharmacology, signaling, and trafficking; reveal
the dissociation of receptor “activation” from desensitization and internal-
ization; and facilitate the discovery that non-G protein effectors mediate
some aspects of GPCR signaling. 23-26 While GPCR signaling texture is a
function of the temporal nature of ligand stimulation as well as the rates
of signaling pathway activation/inactivation, in this chapter, we shall discuss
the role of accessory protein association, specifically the arrestin family, in
regulating diverse modes of GPCR signaling. We shall also outline how
the application of novel systems-level analytical approaches may be valuable