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. | INTRODUCTIONThe $800 human GPCRs transduce sensory inputs and systemic signals into appropriate cellular responses in numerous physiological processes. They recognize a vast diversity of signals ranging from photons, tastants and odours to ions, neurotransmitters, hormones, and cytokines (Harding et al., 2021;Wacker, Stevens, & Roth, 2017).Even though GPCRs represent the primary target of 34% of FDAapproved drugs, more than 220 non-olfactory GPCRs have disease associations which are as yet untapped in clinical research (Hauser, Attwood, Rask-Andersen, Schioth, & Gloriam, 2017;Sriram & Insel, 2018). Despite the diversity of extracellular ligands and physiological roles of GPCRs, these cell surface receptors share a conserved molecular fold and intracellular transducers. Agonist binding stabilizes active conformations of the receptor, facilitating the binding of one or more cytosolic transducer proteins. These include the heterotrimeric G proteins consisting of α, β and γ subunits that dissociate to α and βγ upon activation by the receptor. G proteins comprise 16 distinct α subunits and are divided into four families based on homology and associated downstream signalling pathways: G s (G s and

Pharmacology of Kappa Opioid Receptors: Novel Assays and Ligands

“…Bias factors were considered significantly different from the reference ligand when a ligand’s CL 95% did not include zero. The pharmacological terminology and computations related to biased agonism were consistent with IUPHAR recommendations ( Kolb et al, 2022 ).…”

“…Finally, U-69,593 was also reported to be biased for internalization versus [ 35 S]GTPγS stimulation ( DiMattio et al, 2015 ). These inconsistencies underline the need of adopting more stringent rules in the design and reporting of biased agonism studies; these rules have been recently made available by IUPHAR ( Kolb et al, 2022 ).…”

Common coupling map advances GPCR-G protein selectivity

“…Given that the activity (here log(E max /EC 50 ) values) can vary substantially across G protein family subtypes ( Figure 2 ), this provides cells with a mechanism to shift the system bias toward different intracellular signaling pathways. Such system bias can be modulated further through differential expression of also the receptors and multiple downstream intracellular effectors ( Kolb et al, 2022 ). A recent study found a strong spatial correlation of summed mRNA expression levels for G s -, G i/o -, and G q/11 -linked receptors in humans, macaques, and mice ( Treviño and Manjarrez, 2022 ).…”

Common coupling map advances GPCR-G protein selectivity

“…2), this provides cells with a mechanism to shift the system bias towards different intracellular signaling pathways. Such system bias can be modulated further through differential expression of also the receptors and multiple downstream intracellular effectors (22). A recent study found a strong spatial correlation of summed mRNA expression levels for G s -, G i/o -, and G q/11 -linked receptors in humans, macaques, and mice (23).…”