A Practical Guide to Approaching Biased Agonism at G Protein Coupled Receptors

Abstract

Biased agonism, the ability of a receptor to differentially activate downstream signaling pathways depending on binding of a “biased” agonist compared to a “balanced” agonist, is a well-established paradigm for G protein-coupled receptor (GPCR) signaling. Biased agonists have the promise to act as smarter drugs by specifically targeting pathogenic or therapeutic signaling pathways while avoiding others that could lead to side effects. A number of biased agonists targeting a wide array of GPCRs have been described, primarily based on their signaling in pharmacological assays. However, with the promise of biased agonists as novel therapeutics, comes the peril of not fully characterizing and understanding the activities of these compounds. Indeed, it is likely that some of the compounds that have been described as biased, may not be if quantitative approaches for bias assessment are used. Moreover, cell specific effects can result in “system bias” that cannot be accounted by current approaches for quantifying ligand bias. Other confounding includes kinetic effects which can alter apparent bias and differential propagation of biological signal that results in different levels of amplification of reporters downstream of the same effector. Moreover, the effects of biased agonists frequently cannot be predicted from their pharmacological profiles, and must be tested in the vivo physiological context. Thus, the development of biased agonists as drugs requires a detailed pharmacological characterization, involving both qualitative and quantitative approaches, and a detailed physiological characterization. With this understanding, we stand on the edge of a new era of smarter drugs that target GPCRs.

Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1

“…This is particularly interesting considering that C5a pep behaves as full-agonist in Ca++ mobilization experiment in HMDMs. There is growing evidence for context-specific effector-coupling and functional responses downstream of several GPCRs (20,21). These emerging findings have refined our current understanding of biased signaling by providing substantial evidence of additional levels of complexities in GPCR signaling.…”

Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity

“…Experiments demonstrating that morphine has greater analgesic properties and causes less respiratory depression and constipation in β-arrestin-2 knockout mice have paved the way for trials of a small-molecule μ-opioid receptor agonist that stimulates nearly undetectable levels of β-arrestin recruitment compared to morphine ( Wadman, 2017 ). However, cell-type-specific effects on the differential propagation of signaling responses can affect the interpretation of pharmacological studies, resulting in a need to establish which signaling pathway leads to the desired therapeutic effect in vivo ( Gundry et al., 2017 ). By demonstrating that GoF β-arrestin-biased MC4R alleles in the population are associated with up to a 50% lower risk of obesity and type 2 diabetes, our studies demonstrate that naturally occurring genetic variants in a GPCR can be used to characterize the physiological consequences of biased signaling in humans.…”

Hv1/VSOP regulates neutrophil directional migration and ERK activity by tuning ROS production

“…The distinct results of directional migration in response to fMLF or WKYMVM between these peptides in Hv1/VSOP‐deficient neutrophils might be accounted for by the idea that FPRs activated by these formyl peptides elicit activation of different types of intracellular signals with different strength. It is known that agonist for G protein‐coupled receptors (GPCRs) possesses different abilities to activate different signaling pathways 37,38 : for example, morphine known as partial agonist binding to µ‐opioid receptor has minimal effect on β‐arrestin pathway, 39 but has strong effect on activation of cAMP‐dependent signaling pathway 40 . On the other hand, the other agonist, etorphine known as full agonist, has strong effect on β‐arrestin pathway, leading to receptor internalization, 39 but has minimal effect on activation of cAMP‐dependent signaling pathway 40 .…”