Recent developments in biased agonism

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The classic paradigm of G protein-coupled receptor (GPCR) activation was based on the understanding that agonist binding to a receptor induces or stabilizes a conformational change to an ‘active’ conformation. In the past decade, however, it has been appreciated that ligands can induce distinct ‘active’ receptor conformations with unique downstream functional signaling profiles. Building on the initial recognition of the existence of such ‘biased ligands’, recent years have witnessed significant developments in several areas of GPCR biology. These include increased understanding of structural and biophysical mechanisms underlying biased agonism, improvements in characterization and quantification of ligand efficacy, as well as clinical development of these novel ligands. Here we review recent major developments in these areas over the past several years.

Introduction

That a given G protein coupled receptor (GPCR) can functionally couple to more than one heterotrimeric G protein has been known for many years. However, it was quite surprising when it was first noted in the mid 1990s that, at a single GPCR, different ligands could be ‘biased’ or ‘functionally selective’ toward one or another of these G proteins. Even more surprising were the discoveries a few years later that GPCRs could also signal through β-arrestins and that ligands could be biased toward either a G protein or β-arrestin-mediated pathways. The study of this important and potentially therapeutically relevant phenomenon has exploded over the last several years. Here we review some of the most important recent developments.

In recent years the list of known biased ligands for GPCRs has grown substantially. While the majority of the ligands identified target the binding site of the endogenous ligand for a given receptor (known as orthosteric ligands), recent work has identified a new class of biased ligands, biased allosteric modulators, which bind non-traditional ligand binding sites topographically distinct from the orthosteric binding site [1]. Biased allosteric modulators are characterized by the ability to modulate agonist affinity and/or efficacy toward a biased receptor conformation without affecting receptor activity on their own. In addition to the discovery of a large number of biased ligands acting on multiple receptor types, several major advances have been made regarding the mechanisms underlying biased agonism.

Section snippets

Mechanistic insights into biased agonism

Different receptor states may vary in their ability to activate specific transducers such as G proteins or β-arrestins, as well as to affect transducer functionality in a selective manner. This is supported by the observation that β-arrestin function is dependent on the phosphorylation pattern or ‘barcode’ of the receptor to which it is recruited (Figure 1) [2, 3•, 4, 5]. Nobles et al. [3] demonstrated that β-arrestin recruited to the β2-adrenergic receptor (β2AR) phosphorylated by either G

Quantification of ligand bias

Quantifying ligand bias is important not only to pharmacologically characterize a compound but also in the design of biased drugs, for example, for lead optimization and selection of candidate compounds. While qualitative approaches, such as a comparison of efficacies or an assessment of relative rank order of potencies [15, 16, 17], can identify extremely biased compounds, they usually cannot identify weakly biased compounds or compare different levels of bias between compounds. Thus,

Methodological advances

A common means of determining agonist efficacy for specific transducer pathways is by measurement of second messenger production or downstream signaling events in cell-based assays, such as by monitoring production of cAMP or phosphorylation of ERK1/2. However, downstream signals are often amplified to different extents depending on the assay being used [18•, 20, 21]. Thus, conclusions about transducer efficacy drawn solely based on downstream signaling events may be imprecise and misleading.

Conformational plasticity and multiple ligand-specific conformations of receptor enable biased GPCR signaling

The ‘two-state’ receptor model (inactive and active states) was previously widely accepted to explain GPCR conformation and function. In this model, all ligands with similar functional capabilities stabilize a common receptor conformation. However there is a growing body of evidence supporting ‘multi-state’ models in which GPCRs are dynamic proteins with a high level of plasticity, manifesting in thermally accessible multiple distinct ligand-specific conformations [26, 27•, 28, 29, 30, 31••, 32

Molecular and structural mechanisms underlying biased agonism

Recent structural determination efforts as well as biochemical and biophysical studies are beginning to shed light on the mechanisms by which biased ligands regulate receptor activity. The data suggest that conformational changes in transmembrane domain (TM) 7-helix (H) 8 and extracellular loop (ECL) 2 may all play a role in β-arrestin-mediated signaling, whereas conformational changes in TM3, 5 and 6 as well as intracellular loop (ICL) 3 have been associated with G protein-mediated signaling [

Clinical application

The recognition that biased ligands can activate distinct subsets of downstream signaling cascades relative to unbiased ligands has led to a paradigm shift in terms of how ligand efficacy is defined and characterized. In addition, it has stimulated significant interest in the potential clinical implications of these agents. Indeed recent evidence supports the hypothesis that biased ligands may possess unique pharmacologic properties compared to traditional unbiased ligands.

Over the past few

Conclusions

The classical paradigm of ligand efficacy has undergone major revisions over the past several years with the introduction of concepts such as biased agonism. The recognition that ligands can induce specific receptor activation profiles has stimulated significant interest in obtaining a better understanding of the physiologic, pharmacologic, structural and biophysical mechanisms underlying this phenomenology. Recent research has broadened the understanding of ligand bias and demonstrated that

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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