Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 453

CHAPTER EIGHTEEN

Arrestin Pathways as Drug Targets

‡
* Department of Medicine, Medical University of South Carolina, Charleston, South Carolina USA
† Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston,
South Carolina USA
‡ The Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston,
South Carolina USA

, † ,

Louis M. Luttrell *

Contents
1. Introduction 470

2. Biased GPCR Agonism 471

2.1 Single and multiple active state models of GPCR signaling 471

2.2 Quantifying GPCR ligand “bias” 476

3. The Many Faces of Arrestin-Dependent Biased Agonism 477

3.1 In vitro characterization of arrestin-selective ligand bias 477

3.2 Arrestin-selective ligand bias in vivo 480

3.3 The Screener's dilemma 483

4. The Conserved Arrestin-Dependent Signaling Repertoire 485

4.1 GPCR desensitization 485

4.2 Cell proliferation 486

4.3 Non-proliferative cell growth 487

4.4 Cell survival and apoptosis 488

4.5 Cell migration, chemotaxis, and secretory function 489

5. Conclusions 491

Acknowledgments 492

References 492

Abstract
Our growing appreciation of the pluridimensionality of G protein-coupled receptor
(GPCR) efficacy, coupled with the phenomenon of orthosteric ligand “bias,” offers the
prospect of drugs that selectively modulate different aspects of GPCR function for ther-
apeutic benefit. As the best-studied non-G protein effectors, arrestins have been shown
to mediate a wide range of GPCR signals, and arrestin pathway-selective ligands have
been identified for several receptors. When viewed from the perspective of short term
in vitro assays, such “biased” agonists appear to activate a subset of the response profile
produced by a conventional agonist. Yet, when examined in vivo, the limited data avail-
able suggest that biased ligand effects can diverge from their conventional counter-
parts in ways that cannot be predicted from their in vitro efficacy profile. While some
widely conserved arrestin-regulated biological processes are becoming apparent, what