Community guidelines for GPCR ligand bias: IUPHAR review 32

Abstract

GPCRs modulate a plethora of physiological processes and mediate the effects of one-third of FDA-approved drugs. Depending on which ligand activates a receptor, it can engage different intracellular transducers. This 'biased signalling' paradigm requires that we now characterize physiological signalling not just by receptors but by ligand-receptor pairs. Ligands eliciting biased signalling may constitute better drugs with higher efficacy and fewer adverse effects. However, ligand bias is very complex, making reproducibility and description challenging. Here, we provide guidelines and terminology for any scientists to design and report ligand bias experiments. The guidelines will aid consistency and clarity, as the basic receptor research and drug discovery communities continue to advance our understanding and exploitation of ligand bias. Scientific insight, biosensors, and analytical methods are still evolving and should benefit from and contribute to the implementation of the guidelines, together improving translation from in vitro to disease-relevant in vivo models.

FIGURE 1

Ligand, system and observational bias. Ligand and system bias together determine the functional selectivity (see terminology subsection for definitions). Each type of bias is measured relative to a reference. Observational bias is not of biological origin, but a consequence of assay sensitivity/non‐linearity and the experimental set‐up

FIGURE 2

Bias plot of an equimolar comparison of ligand‐induced activities in two pathways. The plot is adapted from White et al., (2014) in which Salvinorin A was chosen as the reference ligand because it has a bias plot slope close to 1. GR89696 and ICI 199,441 are arrestin‐biased and RB 48 and RB 64 are G protein‐biased. The pathway percent activation could, for example, use ΔΔLog (E_max/EC₅₀) or (ΔΔLog(τ/K_A) values (see Section 6.2 and Box 1)

FIGURE 3

Recommendations to describe the measured pathway process and molecules. (a) Terms to describe the measured pathway process. Also see reviews describing the translation across these levels (Luttrell, Maudsley, & Gesty‐Palmer, 2018), assays (Smith, Lefkowitz, & Rajagopal, 2018) and animal models (Bradley & Tobin, 2016). (b) Data from (Klein Herenbrink et al., 2016) show the relative bias of dopamine D₂ receptor agonists for five pathways (all with dopamine as the reference ligand). The relative order of the ligands changes depending on the measured molecules, even across those participating in the same pathway. This emphasizes that bias should be measured at similar pathway depths (comparably proximal/distal to the receptor), each of which should be defined with respect to the measured entities