Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 454

is lacking at present is a rational framework for relating the in vitro efficacy of a “biased”
agonist to its in vivo actions that will aid drug discovery programs in identifying “ biased ”

ligands with the desired biological effects.

1. INTRODUCTION
The last decade of basic research in G protein-coupled receptor
(GPCR) biology has seen the emergence of two concepts that together have
the potential to foster the development of a new generation of GPCR-based
therapeutics: “pluridimensional” efficacy and “functional selectivity” or
ligand “bias”. Pluridimensional efficacy, a phrase coined by the Michel
Bouvier laboratory in 2006, 1 refers to the capacity of GPCRs to signal
via multiple G protein and non-G protein effectors. 2 The best-studied
non-G protein effectors are the arrestins, which promote homologous
desensitization of G protein-mediated signaling while simultaneously acting
as ligand-regulated scaffolds that recruit additional catalytically active
effectors. 3-5 The simple model is that arrestin binding defines two discrete
GPCR signaling modes, with the unbound receptor functioning primarily
as a guanine nucleotide exchange factor for heterotrimeric G proteins, and
the arrestin-bound “desensitized” receptor serving as the nucleus of a
receptor-arrestin “signalsome” complex.
Functional selectivity, a concept developed by leading GPCR theoreti-
cians including Christopolous and Kenakin, beginning in the 1990s, 6,7
embodies the concept that GPCRs can adopt multiple “active” conforma-
tions that couple the receptor to downstream effectors with different effi-
ciency, and that chemically distinct ligands can affect the conformational
equilibrium of the receptor in ways that produce these distinct active states
in different proportions than the native ligand. 8-10 Functional selectivity
implies that the ligand can control signaling by coupling the receptor to only
a subset of its full complement of effectors, which means that GPCR signal-
ing can be manipulated in ways more complex than simple agonism and
antagonism. In vivo , “biased” ligands would produce mixed effects, directly
activating some downstream pathways while antagonizing the effects of cir-
culating endogenous ligands on others. The promise of biased agonism lies
in this potential to qualitatively change GPCR signaling, permitting adap-
tive or therapeutically beneficial signals to be transmitted while antagonizing
maladaptive ones. 9-11