Systems Analysis of Arrestin Pathway Functions - Progress in Molecular Biology and Translational Science - page 417

1. G PROTEIN-COUPLED RECEPTOR SIGNALING
ACTIVITY
G protein-coupled receptor (GPCR)-mediated signaling represents
one of the most fundamental physiological processes. GPCR signaling has
been demonstrated to regulate almost all forms of cellular communication,
while utilizing an incredibly diverse series of functional mechanisms to do
so. 1 As GPCR biology regulates the vast majority of physiological processes,
it is unsurprising that nearly half of all current pharmacotherapeutics target
this class of proteins. 2 Historically, therapeutic agents that effectively mod-
ulate GPCR biology have been described as agonists, partial agonists, or
antagonists, based on a “two-state” model of receptor function embodied
in the ternary complex model. 3-5 The primary theoretical mechanisms of
GPCR activity involved an appreciation of the receptor system as almost
a binary process. In this simple linear model, the GPCR agonist binds to
and promotes the transition of the receptor from an “off” to an “on” state.
The “on” state is then capable of engaging heterotrimeric (G abg ) guanine
nucleotide-binding proteins, whose dissociated G a and G bg subunits in turn
activate or inhibit various downstream effector molecules. Partial agonists
exert a similar function to agonists, but do not possess as great an efficacy
as the “full” agonist, while antagonists were considered simply able to
unproductively occupy the agonist-binding site. 6 With further develop-
ments in receptor dynamic theory, for example, the extended and cubic ter-
nary complex models, the appreciation of a ligand's nature and eventual
“efficacy” necessitated redefinition. 7,8 These more advanced concepts
expanded the theoretical range of receptor functions beyond the purely
G protein-focused realm. GPCR agonists were initially considered to exert
similarly efficacious effects upon all forms of subsequent receptor activity, for
example, G protein coupling, receptor desensitization, internalization, or
trafficking. Considerable experimental evidence has, however, now demon-
strated the existence of multiple qualitatively distinct forms of ligand efficacy
for a single GPCR type. 9-12 Such data have dramatically altered our appre-
ciation of ligand type, to such an extent that now almost all GPCR-
interacting ligands are considered differentially “agonistic” across multiple
functional efficacies. The etiology of this functional diversity is likely asso-
ciated with the physical speciation of the GPCRs at the plasma membrane
into various stable receptorsome structures. 1,13,14 This functional diversity of