Biased agonism at β-adrenergic receptors

Highlights

• G protein and β-arrestin biased agonists have been characterized for the βARs.

• Biased β-agonists may improve clinical outcomes compared to balanced β-agonists.

• TM VII / ECL movements and GRK interaction are implicated in bias mechanism.

• Biased drug discovery efforts and experimental design require careful consideration.

Abstract

The β-adrenergic receptors (βARs) include three subtypes, β₁, β₂ and β₃. These receptors are widely expressed and regulate numerous physiological processes including cardiovascular and metabolic functions and airway tone. The βARs are also important targets in the treatment of many diseases including hypertension, heart failure and asthma. In some cases, the use of current βAR ligands to treat a disease is suboptimal and can lead to severe side effects. One strategy to potentially improve such treatments is the development of biased agonists that selectively regulate a subset of βAR signaling pathways and responses. Here we discuss the compounds identified to date that preferentially activate a G_s- or β-arrestin-mediated signaling pathway through βARs. Mechanistic insight on how these compounds bias signaling sheds light on the potential development of even more selective compounds that should have increased utility in treating disease.

Introduction

The β-adrenergic receptors (βARs) are a subfamily of G protein-coupled receptors (GPCRs) that are expressed by most cell types in humans [1]. This subfamily consists of three members, β_1, β_2, and β₃AR, and are the targets of the endogenous catecholamines epinephrine and norepinephrine [2,3]. Signaling through βARs regulates a wide variety of physiological processes including cardiac function, airway tone, metabolic function, and others [4]. Due to their ubiquity and key role in human health, the βARs are cornerstone drug targets for a variety of pathologies [5], and drug discovery efforts around these receptors have generated a diverse set of pharmacological agents [6].

Canonically, β-agonists promote receptor mediated G protein activation primarily through G_s to activate the enzyme adenylyl cyclase and increase cAMP production. While there are subtype differences, activated βARs are typically phosphorylated by regulatory kinases such as GPCR kinases (GRKs), and signaling is then terminated via interaction with β-arrestins, a process called desensitization [7]. In recent years, it has become widely accepted that this cycle is an incomplete description of the signaling repertoire of the βARs. An additional role of β-arrestins as signal transducers has been identified [8] and β-arrestins can also mediate receptor internalization (Fig. 1A). While regulation of β₃AR signaling is less well characterized than β₁AR or β₂AR, the β₃AR does not interact with GRKs or β-arrestins and desensitization is observed more often after hours to days rather than minutes [9]. This is due in part to the lack of regulatory kinase phosphorylation sites on the C-terminal tail of the β₃AR that are found in the β₁AR and β₂AR. Evidence suggests that regulation of β₃AR involves downregulation of its mRNA and the receptor protein itself, although this varies across the systems tested and appears to be cell type dependent [9] (Fig. 1B). In addition, βARs have been shown to couple to multiple G proteins, and G protein and β-arrestin interaction with the receptor can be selectively promoted by ligands that stabilize distinct receptor conformations. The selective activation of these pathways is known as biased signaling (Fig. 2). In the early 2000s, the concepts of “pluridimensional efficacy” and “ligand-biased signaling” were first observed for the β₂AR when compounds that were previously characterized as receptor antagonists were reported to have the ability to stimulate β-arrestin-dependent MAP kinase signaling [10] while subsequent studies pioneered the re-classification of β₂AR ligands [11,12]. This review will focus on recent developments in this signaling paradigm at the βARs.