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. 2017 Jan 24:11:17.
doi: 10.3389/fnins.2017.00017. eCollection 2017.

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

Jaimee Gundry  1 , Rachel Glenn  1 , Priya Alagesan  1 , Sudarshan Rajagopal  2
Affiliations

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

Jaimee Gundry et al. Front Neurosci. .

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.

Keywords: G protein coupled receptor; G proteins; GRKs; arrestins; biased agonism.

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Figures

Figure 1
Figure 1
General approach to assessing biased agonism. (A) Considerations for assay development in characterizing biased agonists. (B) Bias plots are generated by converting dose-response data for 2 signaling pathways (G protein and β-arrestin signaling here) to response 1 vs. response 2 data (here β-arrestin vs. G protein signaling). If there is significant amplification between assays, the window for identifying G protein-biased ligands decreases significantly (top panel). To identify both G protein- and β-arrestin-biased, assays with similar levels of amplification should be used (bottom panel). (C) Approaches to quantifying bias based on the presence of binding data (dissociation constant, KD) and whether the concentration-response data is best fit with a Hill coefficient (n) of non-unity. All of these approaches can yield a bias factor, β. For more details on these different approaches, please refer to the text.
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