Location bias: A “Hidden Variable” in GPCR pharmacology

Abstract

G protein‐coupled receptors (GPCRs) are the largest family of transmembrane receptors and primarily signal through two main effector proteins: G proteins and β‐arrestins. Many agonists of GPCRs promote “biased” responses, in which different cellular signaling pathways are activated with varying efficacies. The mechanisms underlying biased signaling have not been fully elucidated, with many potential “hidden variables” that regulate this behavior. One contributor is “location bias,” which refers to the generation of unique signaling cascades from a given GPCR depending upon the cellular location at which the receptor is signaling. Here, we review evidence that GPCRs are expressed at and traffic to various subcellular locations and discuss how location bias can impact the pharmacologic properties and characterization of GPCR agonists. We also evaluate how differences in subcellular environments can modulate GPCR signaling, highlight the physiological significance of subcellular GPCR signaling, and discuss the therapeutic potential of exploiting GPCR location bias.

Keeping pace: the primary cilium as the conducting baton of the islet

“…Intriguingly, GPR120 localises to primary cilia and this localisation is required for augmentation of insulin secretion, while GPR40 is plasma membrane localised and operates independently of the cilium [ 8 ], suggesting parallel processing of a common signal. However, such parallel processing may not even require distinct receptor isoforms but instead depend on differences in receptor activation and coupling in the ciliary microenvironment [ 19 ]. For example, 1 nmol/l insulin was sufficient to induce insulin receptor substrate 1 (IRS1) phosphorylation in the primary cilia of adipocytes, while 100 nmol/l was required for phosphorylation of plasma membrane-localised IRS1 [ 20 ].…”

G Protein-Coupled Receptors: A Century of Research and Discovery

“…137,138 A related concept is that of location bias (Figure 4), where different ligands promote receptor activation in different subcellular locations, resulting in distinct cellular and physiological effects. 139 As bias allows for the selection of signaling pathways to be activated downstream of a receptor, biased ligands have the potential to activate beneficial signaling pathways while limiting off-target effects at a given GPCR. Thus, drug development of biased agonists is a very active area of research.…”